CN105732576B - The chloro- 3- of 2- (1H- benzimidazolyl-2 radicals-yl)-quinoline preparation methods and application - Google Patents
The chloro- 3- of 2- (1H- benzimidazolyl-2 radicals-yl)-quinoline preparation methods and application Download PDFInfo
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- CN105732576B CN105732576B CN201610078947.3A CN201610078947A CN105732576B CN 105732576 B CN105732576 B CN 105732576B CN 201610078947 A CN201610078947 A CN 201610078947A CN 105732576 B CN105732576 B CN 105732576B
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- GOTOEYUPIUTKIN-UHFFFAOYSA-N CC(C=C1C=C2c3nc(ccc(Br)c4)c4[nH]3)=CCC1N=C2Cl Chemical compound CC(C=C1C=C2c3nc(ccc(Br)c4)c4[nH]3)=CCC1N=C2Cl GOTOEYUPIUTKIN-UHFFFAOYSA-N 0.000 description 1
- AHYKWKKOWLFEPH-UHFFFAOYSA-N CCc(ccc1n2)cc1cc(C1=NC3C=CC(F)=CC3N1)c2Cl Chemical compound CCc(ccc1n2)cc1cc(C1=NC3C=CC(F)=CC3N1)c2Cl AHYKWKKOWLFEPH-UHFFFAOYSA-N 0.000 description 1
- RUFZKBHRVXOHCO-UHFFFAOYSA-N Cc(cc1CC=C2c3cc(ccc(F)c4)c4[nH]3)ccc1N=C2Cl Chemical compound Cc(cc1CC=C2c3cc(ccc(F)c4)c4[nH]3)ccc1N=C2Cl RUFZKBHRVXOHCO-UHFFFAOYSA-N 0.000 description 1
- FERWNLRGLPRIAG-UHFFFAOYSA-N Cc(ccc1n2)cc1cc(-c1nc3cc(C)c(C)cc3[nH]1)c2Cl Chemical compound Cc(ccc1n2)cc1cc(-c1nc3cc(C)c(C)cc3[nH]1)c2Cl FERWNLRGLPRIAG-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
Abstract
The invention discloses a kind of 2 chlorine, 3 (2 base of 1H benzimidazoles) quinoline preparation method and applications.The preparation method of the derivative is：Take 2 chlorine, 3 carboxaldehyde radicals quinoline and O-phenylene diamine derivatives to be dissolved in organic solvent, reacted under heating condition to get.More common 5 FU of antitumor drug of certain derivatives in derivative of the present invention compares active higher with cis-platinum, lower to people's normal cell lines of human liver 7702 toxicity of HL.2 chlorine 3 (2 base of 1H benzimidazoles) quinoline of the present invention has the structure as shown in following formula (I)：Wherein, R1For hydrogen, methyl, methoxyl group or and R2Form 1,2 methylene-dioxies；R2For hydrogen or and R1Form 1,2 methylene-dioxies；R3For hydrogen, methyl, methoxyl group, fluorine-based, chloro, bromo, nitro or trifluoromethyl；R4For hydrogen, methyl, methoxyl group or chloro.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to the chloro- 3- of 2- (1H- benzimidazolyl-2 radicals-yl)-quinoline its
Preparation method and application.
Background technology
Cancer be seriously endanger people's life one of intractable diseases, the drug for researching and developing anti-curing cancers be contemporary scientific man urgently
One of global problem to be captured.
Quinoline is a kind of important nitrogen heterocyclic.Studies have shown that quinoline and its derivates are with such as anti-oxidant, anti-
The wide spectrum biological activities such as tumour, anti-inflammatory, anti-malarial, therefore the design synthesis of quinoline receives the highest attention of people
(DeRuiter,J.Brubaker,A.N.；Whitmer,W.L.；Stein,J.L.；J.Med.Chem.1986,29,2024.；
Zhang,Y.；Fang,Y.L.；Liang,H.；Wang,H.S.；Hu,K.；Liu,X.X.；Yi,X.H.；Peng,
Y.Bioorg.Med.Chem.2013,23,107.；Hewawasam,P.；Fan,W.；Knipe,J.；Moon,L.S.；
Boissard,G.C.；Gribkoff,K.V.；Starett,E.J.Bioorg.Med.Chem.Lett.2002,12,1779.).
Benzimidazole and its derivative show good anti-oxidant, antitumor activity (Craigo, W.A.；Lesueur,B.W.；
Skibo,E.B.J.Med.Chem.1999,42,3324；Gudmundsson,K.S.；Tidwell,J.；Lippa,N.；
Koszalka,G.W.；Van D.N.；Ptak,R.G.；Drach,J.C.；Townsend,L.B.J.Med.Chem.2000,43,
2464).But it has not yet to see in 3 upper functional groups benzimidazoles that introduce of chinoline backbone to prepare 2- chloro- 3- (1H- benzene
And imidazoles -2- bases)-quinoline open report.
Invention content
The technical problem to be solved in the present invention is to provide a series of 2- of structure novels chloro- 3- (1H- benzimidazolyl-2 radicals-
Base)-quinoline and their preparation method and application.
The present invention relates to compound shown in lower formula (I) or its pharmaceutically acceptable salts：
Wherein,
R1For hydrogen, methyl, methoxyl group or and R2Form 1,2- methylene-dioxies；
R2For hydrogen or and R1Form 1,2- methylene-dioxies；
R3For hydrogen, methyl, methoxyl group, fluorine-based, chloro, bromo, nitro or trifluoromethyl；
R4For hydrogen, methyl, methoxyl group or chloro.
The preparation method of compound shown in above-mentioned formula (I) is：Take compound shown in compound and formula (III) shown in formula (II)
It is dissolved in organic solvent, is reacted under heating condition to get to target product；
Wherein,
R1For hydrogen, methyl, methoxyl group or and R2Form 1,2- methylene-dioxies；
R2For hydrogen or and R1Form 1,2- methylene-dioxies；
R3For hydrogen, methyl, methoxyl group, fluorine-based, chloro, bromo, nitro or trifluoromethyl；
R4For hydrogen, methyl, methoxyl group or chloro.
In preparation method of the present invention, the substance of compound shown in compound and formula (III) shown in the formula (II)
The ratio between amount preferably 1：0.9~1.1.Reaction equally can also when the dosage of the compound shown in the formula (III) is more than above range
Target product is generated, can only cause postorder separating difficulty to increase, can also reduce the product of target product.
In preparation method of the present invention, compound shown in the formula (II) can be specifically the chloro- quinolines of 3- carboxaldehyde radicals -2-
Quinoline, 3- carboxaldehyde radicals -6- methyl -2- chlorine-quinolines, 3- carboxaldehyde radicals -6- methoxyl group -2- chlorine-quinolines or 3- carboxaldehyde radicals -6,7- methylenes two
Oxygroup -2- chlorine-quinolines.Compound can be synthesized with designed, designed synthetic route shown in above-mentioned formula (II), can also refer to this
Article (Zhang, the Y. that inventor delivers before；Fang,Y.L.；Liang,H.；Wang,H.S.；Hu,K.；Liu,X.X.；Yi,
X.H.；Peng, Y.Bioorg.Med.Chem.2013,23,107) it is prepared, specific synthetic route is：
Wherein, work as R1For H, R2For H when, product be the chloro- 3- carboxaldehyde radicals quinoline of 2-；Work as R1For methyl, R2For H when, product is
The chloro- 3- carboxaldehyde radicals -6- methylquinolines of 2-；Work as R1For methoxyl group, R2For H when, product be the chloro- 3- carboxaldehyde radicals -6- methoxyl group quinolines of 2-
Quinoline；And work as R1With R2When forming 1,2- methylene-dioxies, product is chloro- 3- carboxaldehyde radicals -6, the 7- methylene-dioxy quinoline of 2-.
In preparation method of the present invention, compound shown in the formula (III) can be that unsubstituted o-phenylenediamine derives
Object, 4 mono-substituted O-phenylene diamine derivatives or 4,5 disubstituted O-phenylene diamine derivatives.Specifically, it can be adjacent benzene two
Amine, 4- fluorine o-phenylenediamine, 4- chlorine o-phenylenediamine, 4- bromines o-phenylenediamine, 4-nitro-o-phenylenediamine, 4- trifluoromethyls o-phenylenediamine,
4,5- dimethyl o-phenylenediamine, 4,5- dimethoxys o-phenylenediamine or 4,5- dichloride base o-phenylenediamines etc..
In preparation method of the present invention, the organic solvent can be alcohols solvent and/or aprotic polar solvent.
Wherein, the alcohols solvent can be selected from volumetric concentration be 80~100% methanol, volumetric concentration be 80~100%
The combination of one or more of ethyl alcohol, normal propyl alcohol, n-butanol and ethylene glycol monomethyl ether；The aprotic polar solvent can
To be the combination of one or more of N,N-dimethylformamide, dimethyl sulfoxide (DMSO), tetrahydrofuran and toluene.When organic
Combination more than two be selected as in above-mentioned alcohols solvent kind substance of solvent, or in above-mentioned aprotic polar solvent
Combinations more than two kinds of substances, or for selected from one or more of alcohols solvent with selected from aprotic polar solvent
One or more of combination when, the proportioning between them can be arbitrary proportioning.
In preparation method of the present invention, the dosage of polar solvent can determine as needed, it is generally the case that 1mmol's
Compound is dissolved with the organic solvent of 5~15mL shown in the formula (III) of compound and 0.9~1.1mmol shown in formula (II).
In specific dissolving step, compound shown in compound shown in formula (II) and formula (III) can be dissolved with partial solvent respectively, then
Mix reaction；Also molten added with solvent again after compound shown in compound shown in formula (II) and formula (III) being mixed
Solution.
In preparation method of the present invention, the reaction carries out usually in conventional reactor, and whether reaction can adopt completely
With thin-layer chromatography tracing detection.In order to accelerate reaction speed, reaction is preferably in 50 DEG C to organic solvent of boiling point temperature range
It is interior to carry out and (reacted with this condition to the time for usually requiring 5~10h completely), more preferably in 70 DEG C to organic solvent of boiling
It is carried out in point temperature range.After completion of the reaction, gained reactant filters, and collects solid, and washing (usually uses absolute ethyl alcohol, nothing
The washings such as water methanol or water), dry (it can be with naturally dry or drying, when using drying mode, drying temperature is to be no more than 50 DEG C
It is advisable), as final target product.
The particularly preferably described reaction of speed in order to further speed up reaction is carried out under conditions of heating and ultrasound.Institute
The frequency for stating ultrasound is preferably 40~65kHz, and power is preferably 240~600W, more preferably 420~600W；When reaction is upper
It states under ultrasound condition and temperature is when 70 DEG C to organic solvent of boiling point temperature range carries out, reaction to about needing 1~2h completely.
The invention also includes compound or its pharmaceutically acceptable salts shown in above-mentioned formula (I) in the preparation of antitumor drugs
Application.
The present invention further comprises using compound or its pharmaceutically acceptable salt shown in above-mentioned formula (I) as active ingredient system
Standby antitumor drug.
Compared with prior art, the present invention provides a series of chloro- 3- of the 2- of structure novels (1H- benzimidazolyl-2 radicals-yl)-
Quinoline, short preparation period, post-processing is simple, at low cost, and gained derivative purity is high, stable quality；Applicant
It has also been found that derivative of the present invention effectively improves the antitumor activity of the chloro- 3- carboxaldehyde radicals quinoline of 2-, swell with commonly anti-
Tumor medicine 5-FU is compared with cis-platinum, the active higher of certain derivatives and, tool lower to the toxicity of people's normal cell lines of human liver HL-7702
There is preferable potential medical value, is expected to be used for the preparation of various antitumor drugs.
Specific implementation mode
With reference to specific embodiment, the present invention is described in further detail, to more fully understand present disclosure, but
The present invention is not limited to following embodiments.
In following embodiment, the chloro- 3- carboxaldehyde radicals quinoline compounds of involved raw material 2- 1 indicate that raw material 2- is chloro-
3- carboxaldehyde radicals -6- methylquinolines compound 2 indicates, the chloro- 3- carboxaldehyde radicals -6- methoxy quinolines compounds of raw material 2- 3 indicate,
The chloro- 3- carboxaldehyde radicals -6,7- methylene-dioxies quinoline of raw material 2- (is also referred to as chloro- 3- carboxaldehyde radicals-[1,3] dioxolanes of 2- simultaneously [6,7-g]
Quinoline) it is indicated with compound 4, their preparation method difference is as follows：
1, the preparation of compound 1：By the POCl of 3.5mL DMF and 17mL3After stirring evenly, 2.03g acetyl is added in mixing
Aniline is warming up to 90 DEG C, is heated to reflux 16h, is poured into a large amount of ice water after cooling, filters, obtain compound 1, yield 88%.
Compound 1:1H NMR(500MHz,DMSO-d6)δ:10.49 (s, 1H, CHO), 8.79 (s, 1H, C=CH), 8.11
(d, J=7.9Hz, 1H, Ar-H), 7.95 (t, J=7.8Hz, 1H, Ar-H), 7.89 (d, J=8.3Hz, 1H, Ar-H), 7.68
(t, J=8.0Hz, 1H, Ar-H)；MS m/z:192[M+H]+.
2, the preparation of compound 2：The synthesis step of reference compound 1 can be made with replacing antifebrin to the first and second anilides
Compound 2, yield, 85%.
Compound 2:1H NMR(500MHz,DMSO-d6)δ:10.61 (s, 1H, CHO), 8.80 (s, 1H, C=CH), 8.12
(d, J=7.8Hz, 1H, Ar-H), 8.01 (t, J=7.9Hz, 1H, Ar-H), 7.75 (d, J=8.3Hz, 1H, Ar-H), 2.61
(s,CH3)；MS m/z:206[M+H]+.
3, the preparation of compound 3：The synthesis step of reference compound 1 replaces antifebrin with methacetin,
It can be made compound 3, yield, 80%.
Compound 3:1H NMR(500MHz,DMSO-d6)δ:10.61 (s, 1H, CHO), 9.01 (s, 1H, C=CH), 8.11
(d, J=7.8Hz, 1H, Ar-H), 7.71 (t, J=7.9Hz, 1H, Ar-H), 7.65 (d, J=8.3Hz, 1H, Ar-H), 3.77
(s,OCH3)；MS m/z:222[M+H]+.
4, the preparation of compound 4：The synthesis step of reference compound 1 replaces second with 3,4- methylene-dioxy antifebrins
Anilide, can be made compound 4, yield, and 75%.
Compound 4:1H NMR(500MHz,DMSO-d6)δ:10.35 (s, 1H, CHO), 8.41 (s, 1H, C=CH), 7.70
(d, J=7.5Hz, 1H, Ar-H), 7.45 (t, J=7.8Hz, 1H, Ar-H), 5.97 (s, 2H, OCH2O)；MS m/z:236[M+
H]+.
Embodiment 1：The chloro- 3- of 2- (5,6- dimethyl -1H- benzimidazolyl-2 radicals-yl) -6- methoxy quinolines (compound a)
It prepares
Weigh Compound 30.2g (0.90mmol), 4,5- dimethyl o-phenylenediamine 0.122g (0.90mmol), 6mL are anhydrous
Methanol is placed in pressure tube (tube sealing), is stirred to react under the conditions of 80 DEG C to complete (TLC tracing detections, about 9h), after cooling
It filters, is washed with absolute ethyl alcohol, obtain compound a (faint yellow solid) 0.179g, yield 59%.
Compound a：Yields 59%,1H NMR(500MHz,DMSO-d6)δ12.88(s,1H),8.84(s,1H),7.96
(d, J=9.2Hz, 1H), 7.60 (s, 1H), 7.55 (d, J=9.1Hz, 1H), 7.46 (s, 2H), 3.93 (s, 3H), 2.36 (s,
6H)；13C NMR(126MHz,DMSO-d6)δ158.70,147.27,144.89,143.27,140.29,131.65,129.64,
128.16,125.06,124.67,106.81,56.24,20.49.MS m/z:338[M+H]+.
Accordingly, it can be determined that above compound a is the chloro- 3- of 2- (5,6- dimethyl -1H- benzimidazolyl-2 radicals-yl) -6- methoxyl groups
Quinoline, structural formula are shown below：
Embodiment 2：The chloro- 3- of 2- (5,6- dimethyl -1H- benzimidazolyl-2 radicals-yl)-[1,3] dioxolanes simultaneously [6,7-g] quinoline
Quinoline (the preparation of compound b)
Weigh Compound 40.2g (0.85mmol), 4,5- dimethyl o-phenylenediamine 0.116g (0.85mmol), 6mL are anhydrous
Methanol is placed in pressure tube (tube sealing), is stirred to react under the conditions of 80 DEG C to complete (TLC tracing detections, about 7.5h), cooling
After filter, washed with absolute ethyl alcohol, obtain compound b (faint yellow solid) 0.192g, yield 64.5%.
Compound b：Yields 64.5%,1H NMR(500MHz,DMSO-d6)δ12.19(s,1H),8.75(s,1H),
7.54 (s, 1H), 7.44 (d, J=5.6Hz, 3H), 6.29 (s, 2H), 2.35 (s, 6H)；13CNMR(126MHz,DMSO-d6)δ
152.94,149.07,147.41,145.96,145.09,140.00,131.45,124.15,122.76,104.53,103.47,
103.20,20.4.MS m/z:352[M+H]+.
Accordingly, it can be determined that above compound b is the chloro- 3- of 2- (5,6- dimethyl -1H- benzimidazolyl-2 radicals-yl)-[1,3] two
Simultaneously [6,7-g] quinoline, structural formula are shown below butyl oxide link：
Embodiment 3：The chloro- 3- of 2- (5,6- dimethyl -1H- benzimidazolyl-2 radicals-yl)-quinoline (preparation of compound c)
Weigh Compound 10.2g (1.05mmol), 4,5- dimethyl o-phenylenediamine 0.143g (1.05mmol), 2mLN, N-
Dimethylformamide, 2mL dimethyl sulfoxide (DMSO)s and 2mL toluene are placed in pressure tube (tube sealing), are 95 DEG C, supersonic frequency in temperature
Reaction filters, with nothing to complete (TLC tracing detections, about 1.5h) after cooling under conditions of being 540W for 40kHz, ultrasonic power
Water-ethanol washs, and obtains compound c (faint yellow solid) 0.287g, yield 89.1%.
Compound c：Yields 89.1%,1H NMR(500MHz,DMSO-d6)δ12.68(s,1H),8.97(s,1H),
8.20 (s, 1H), 8.06 (s, 1H), 7.92 (d, J=8.4Hz, 1H), 7.75 (d, J=8.1Hz, 1H), 7.45 (s, 2H), 2.36
(s,6H)；13C NMR(126MHz,DMSO-d6)δ147.68,147.21,141.58,132.36,129.01,128.44,
128.16,126.87,125.14,20.50.MS m/z:308[M+H]+.
Accordingly, it can be determined that above compound c is the chloro- 3- of 2- (5,6- dimethyl -1H- benzimidazolyl-2 radicals-yl)-quinoline,
Structural formula is shown below：
Embodiment 4：The chloro- 3- of 2- (5,6- dimethyl -1H- benzimidazolyl-2 radicals-yl) -6- methylquinolines (system of compound d)
It is standby
With reference to the method for embodiment 1, Weigh Compound 20.2g (0.98mmol), 4,5- dimethyl o-phenylenediamines 0.132g
(0.98mmol), 6mL absolute methanols are placed in pressure tube (tube sealing), are stirred to react under the conditions of 80 DEG C to (TLC is tracked completely
Detection, about 8h), it is filtered after cooling, is washed with absolute ethyl alcohol, obtain compound d (faint yellow solid) 0.183g, yield
58.1%.
Compound d：Yields 58.1%,1H NMR(500MHz,DMSO-d6)δ12.66(s,1H),8.84(s,1H),
7.94(s,2H),7.84(s,1H),7.46(s,2H),2.54(s,3H),2.36(s,6H)；13C NMR(126MHz,DMSO-d6)
δ147.32,146.78,145.84,140.84,138.21,134.49,127.90,127.54,126.88,125.09,21.62,
20.50.MS m/z:322[M+H]+.
Accordingly, it can be determined that above compound d is the chloro- 3- of 2- (5,6- dimethyl -1H- benzimidazolyl-2 radicals-yl) -6- methyl quinolines
Quinoline, structural formula are shown below：
Embodiment 5：The chloro- 3- of 2- (5- methoxyl groups -1H- benzimidazolyl-2 radicals-yl)-quinoline (preparation of compound e)
With reference to the method for embodiment 1, Weigh Compound 10.2g (1.05mmol), 4- methoxyl group o-phenylenediamines 0.16g
Methanol, 2mL dimethyl sulfoxide (DMSO)s and the 2mL toluene that (1.05mmol), 4mL volumetric concentrations are 90% are placed in pressure tube (envelope
Pipe), it is stirred to react under the conditions of 60 DEG C to complete (TLC tracing detections, about 9h), is filtered after cooling, washed, obtained with absolute ethyl alcohol
To compound e (faint yellow solid) 0.187g, yield 57.6%.
Compound e：Yields 57.6%,1H NMR(500MHz,DMSO-d6)δ12.77(s,1H),8.98(s,1H),
8.20 (s, 1H), 8.06 (d, J=8.3Hz, 1H), 7.93 (d, J=8.4Hz, 1H), 7.76 (s, 1H), 7.62 (s, 1H), 7.19
(s,1H),6.92(s,1H),3.84(s,3H)；13C NMR(126MHz,DMSO-d6)δ147.58,147.20,141.52,
132.39,129.11,129.01,128.46,128.15,126.86,124.97,56.00.MS m/z:310[M+H]+.
Accordingly, it can be determined that above compound e is the chloro- 3- of 2- (5- methoxyl groups -1H- benzimidazolyl-2 radicals-yl)-quinoline, knot
Structure formula is shown below：
Embodiment 6：The chloro- 3- of 2- (5- methoxyl groups -1H- benzimidazolyl-2 radicals-yl) -6- methylquinolines (preparation of compound f)
With reference to the method for embodiment 3, Weigh Compound 20.2g (0.98mmol), 4- methoxyl group o-phenylenediamines 0.15g
The ethyl alcohol that (0.98mmol), 15mL volumetric concentrations are 80% is placed in pressure tube (tube sealing), is 85 DEG C, supersonic frequency in temperature
Reaction filters, use is anhydrous to complete (TLC tracing detections, about 2h) after cooling under conditions of being 540W for 40kHz, ultrasonic power
Methanol washs, and obtains compound f (faint yellow solid) 0.279g, yield 88.3%.
Compound f：Yields 88.3%,1H NMR(500MHz,DMSO-d6)δ12.76(s,1H),8.85(s,1H),
7.96 (s, 2H), 7.76 (d, J=8.6Hz, 1H), 7.59 (d, J=8.2Hz, 1H), 7.16 (s, 1H), 6.91 (s, 1H), 3.84
(s,3H),2.55(s,3H)；13C NMR(126MHz,DMSO-d6)δ146.69,145.84,140.84,138.25,134.54,
131.97,129.13,127.91,127.55,126.88,124.91,55.99,21.62.MS m/z:324[M+H]+.
Accordingly, it can be determined that above compound f is the chloro- 3- of 2- (5- methoxyl groups -1H- benzimidazolyl-2 radicals-yl) -6- methyl quinolines
Quinoline, structural formula are shown below：
Embodiment 7：The chloro- 3- of 2- (5- methoxyl groups -1H- benzimidazolyl-2 radicals-yl) -6- methoxy quinolines (system of compound g)
It is standby
With reference to the method for embodiment 1, Weigh Compound 30.2g (0.90mmol), 4- methoxyl group o-phenylenediamines 0.14g
(0.90mmol), 5mL absolute methanols are placed in pressure tube (tube sealing), are stirred to react under the conditions of 60 DEG C to (TLC is tracked completely
Detection, about 10h), it is filtered after cooling, is washed with absolute ethyl alcohol, obtain compound g (faint yellow solid) 0.179g, yield
58.8%.
Compound g：Yields 58.8%,1H NMR(500MHz,DMSO-d6)δ12.75(s,1H),8.84(s,1H),
7.97 (d, J=9.1Hz, 1H), 7.59 (s, 1H), 7.58 (s, 1H), 7.56 (d, J=9.1Hz, 1H), 7.17 (s, 1H), 6.92
(s,1H),3.79(s,6H)；13C NMR(126MHz,DMSO-d6)δ158.70,156.61,144.83,143.25,140.20,
129.64,128.19,125.07,124.68,106.78,56.24,55.99.MS m/z:340[M+H]+.
Accordingly, it can be determined that above compound g is the chloro- 3- of 2- (5- methoxyl groups -1H- benzimidazolyl-2 radicals-yl) -6- methoxyl group quinolines
Quinoline, structural formula are shown below：
Embodiment 8：The chloro- 3- of 2- (5- methoxyl groups -1H- benzimidazolyl-2 radicals-yl)-[1,3] dioxolanes simultaneously [6,7-g] quinoline
(the preparation of compound h)
With reference to the method for embodiment 3, Weigh Compound 40.2g (0.85mmol), 4- methoxyl group o-phenylenediamines 0.13g
The methanol that (0.85mmol), 6mL volumetric concentrations are 95% is placed in pressure tube (tube sealing), is 85 DEG C, supersonic frequency in temperature
Reaction is filtered after cooling, is washed with water to complete (TLC tracing detections, about 2h) under conditions of being 600W for 65kHz, ultrasonic power
It washs, obtains compound h (faint yellow solid) 0.269g, yield 89.7%.
Compound h：Yields 89.7%,1H NMR(500MHz,DMSO-d6)δ12.56(s,1H),8.76(s,1H),
7.57 (d, J=8.8Hz, 1H), 7.55 (s, 1H), 7.44 (s, 1H), 7.16 (s, 1H), 6.91 (d, J=8.8Hz, 1H), 6.29
(s,2H),3.83(s,3H)；13C NMR(126MHz,DMSO-d6)δ156.61,153.02,149.13,146.02,144.98,
140.01,124.15,112.85,104.56,103.49,103.24,56.00.MS m/z:355[M+H]+.
Accordingly, it can be determined that above compound h is the chloro- 3- of 2- (5- methoxyl groups -1H- benzimidazolyl-2 radicals-yl)-[1,3] dioxy
Simultaneously [6,7-g] quinoline, structural formula are shown below penta ring：
Embodiment 9：The chloro- 3- of 2- (bis- chloro- 1H- benzimidazolyl-2 radicals-yls of 5,6-)-quinoline (preparation of compound i)
With reference to the method for embodiment 1, Weigh Compound 10.2g (1.05mmol), 4,5-, bis- chloro- 1,2- o-phenylenediamines 0.2g
(1.15mmol), 10mL ethylene glycol monomethyl ethers are placed in pressure tube (tube sealing), are stirred to react under the conditions of 80 DEG C to complete (TLC
Tracing detection, about 8h), it is filtered after cooling, is washed with absolute ethyl alcohol, obtain compound i (faint yellow solid) 0.201g, yield
55.1%.
Compound i：Yields 55.1%,1H NMR(500MHz,DMSO-d6)δ13.29(s,1H),9.03(s,1H),
8.21 (s, 1H), 8.08 (d, J=8.5Hz, 1H), 7.99 (s, 2H), 7.96 (d, J=8.4Hz, 1H), 7.78 (s, 1H)；13C
NMR(126MHz,DMSO-d6)δ150.82,147.49,147.33,142.28,132.86,131.97,129.18,128.65,
128.21,126.71,124.04.MS m/z:348[M+H]+.
Accordingly, it can be determined that above compound i is the chloro- 3- of 2- (5,6- bis- chloro- 1H- benzimidazolyl-2 radicals-yl)-quinoline, knot
Structure formula is shown below：
Embodiment 10：The chloro- 3- of 2- (bis- chloro- 1H- benzimidazolyl-2 radicals-yls of 5,6-) -6- methylquinolines (preparation of compound j)
With reference to the method for embodiment 3, Weigh Compound 20.2g (0.98mmol), 4,5-, bis- chloro- 1,2- o-phenylenediamines
0.19g (1.07mmol), 1mL absolute methanols, 3mL absolute ethyl alcohols and 2mL normal propyl alcohols are placed in pressure tube (tube sealing), in temperature
For 85 DEG C, supersonic frequency 50kHz, ultrasonic power be 400W under conditions of reaction to complete (TLC tracing detections, about 2h), it is cold
But it filters, is washed with absolute ethyl alcohol afterwards, obtain compound j (faint yellow solid) 0.319g, yield 90.2%.
Compound j：Yields 90.2%,1H NMR(500MHz,DMSO-d6)δ13.26(s,1H),8.88(s,1H),
7.96 (d, J=8.6Hz, 2H), 7.94 (s, 2H), 7.78 (s, 1H), 2.54 (s, 3H)；13C NMR(126MHz,DMSO-d6)δ
150.92,146.41,146.14,141.46,138.44,134.94,127.94,127.66,126.71,123.99,
21.61.MS m/z:362[M+H]+.
Accordingly, it can be determined that above compound j is the chloro- 3- of 2- (5,6- bis- chloro- 1H- benzimidazolyl-2 radicals-yl) -6- methyl quinolines
Quinoline, structural formula are shown below：
Embodiment 11：The chloro- 3- of 2- (bis- chloro- 1H- benzimidazolyl-2 radicals-yls of 5,6-) -6- methoxy quinolines (system of compound k)
It is standby
With reference to the method for embodiment 1, Weigh Compound 30.2g (0.90mmol), 4,5-, bis- chloro- 1,2- o-phenylenediamines
0.18g (0.99mmol), 5mL normal propyl alcohols are placed in pressure tube (tube sealing), are stirred to react under the conditions of 80 DEG C to complete (TLC
Tracing detection, about 8h), it is filtered after cooling, is washed with absolute ethyl alcohol, obtain compound k (faint yellow solid) 0.195g, yield
57.5%.
Compound k：Yields 57.5%,1H NMR(500MHz,DMSO-d6)δ13.16(s,1H),8.88(s,1H),
7.99(s,1H),7.97(s,2H),7.60(s,1H),7.57(s,1H),3.94(s,3H)；13C NMR(126MHz,DMSO-d6)
δ158.79,150.93,144.54,143.54,140.84,129.69,128.05,125.54,125.11,124.13,
106.91,56.28.MS m/z:378[M+H]+.
Accordingly, it can be determined that above compound k is the chloro- 3- of 2- (5,6- bis- chloro- 1H- benzimidazolyl-2 radicals-yl) -6- methoxyl group quinolines
Quinoline, structural formula are shown below：
Embodiment 12：The chloro- 3- of 2- (bis- chloro- 1H- benzimidazolyl-2 radicals-yls of 5,6-)-[1,3] dioxolanes simultaneously [6,7-g] quinoline
Quinoline (the preparation of compound l)
With reference to the method for embodiment 3, Weigh Compound 40.2g (0.85mmol), 4,5-, bis- chloro- 1,2- o-phenylenediamines
0.17g (0.94mmol), 6mL absolute methanols are placed in pressure tube (tube sealing), temperature be 85 DEG C, supersonic frequency 40kHz,
Reaction filters after cooling to complete (TLC tracing detections, about 2h), is washed with water, is changed under conditions of ultrasonic power is 600W
Close object l (faint yellow solid) 0.295g, yield 88.9%.
Compound l：Yields 88.9%,1H NMR(500MHz,DMSO-d6)δ12.89(s,1H),8.80(s,1H),
7.95(s,2H),7.56(s,1H),7.44(s,1H),6.31(s,2H)；13C NMR(126MHz,DMSO-d6)δ153.32,
151.05,149.23,146.38,144.79,140.46,131.96,129.12,124.07,121.69,104.58,103.57,
103.33.MS m/z:392[M+H]+.
Accordingly, it can be determined that above compound l is the chloro- 3- of 2- (5,6- bis- chloro- 1H- benzimidazolyl-2 radicals-yl)-[1,3] dioxy
Simultaneously [6,7-g] quinoline, structural formula are shown below penta ring：
Embodiment 13：The chloro- 3- of 2- (the bromo- 1H- benzimidazolyl-2 radicals-yls of 5-)-quinoline (preparation of compound m)
With reference to the method for embodiment 1, bromo- 1, the 2- o-phenylenediamines 0.21g of Weigh Compound 10.2g (1.05mmol), 4-
(1.15mmol), 6mL volumetric concentrations be 85% ethyl alcohol be placed in pressure tube (tube sealing), be stirred to react under the conditions of 80 DEG C to
(TLC tracing detections, about 8h) completely filters after cooling, is washed with absolute ethyl alcohol, obtain compound m (faint yellow solid)
0.208g, yield 55.4%.
Compound m：Yields 55.4%,1H NMR(500MHz,DMSO-d6)δ13.14(s,1H),9.02(s,1H),
8.21 (d, J=8.4Hz, 1H), 8.08 (d, J=8.5Hz, 1H), 7.96 (s, 2H), 7.78 (d, J=7.5Hz, 1H), 7.72
(s, 1H), 7.67 (d, J=5.4Hz, 1H)；13C NMR(126MHz,DMSO-d6)δ147.44,132.75,131.99,
129.13,128.61,128.20,126.77,124.40,114.24.MS m/z:358[M+H]+.
Accordingly, it can be determined that above compound m is the chloro- 3- of 2- (the bromo- 1H- benzimidazolyl-2 radicals-yls of 5-)-quinoline, structural formula
It is shown below：
Embodiment 14：The chloro- 3- of 2- (the bromo- 1H- benzimidazolyl-2 radicals-yls of 5-) -6- methylquinolines (preparation of compound n)
With reference to the method for embodiment 3, bromo- 1, the 2- o-phenylenediamines 0.2g of Weigh Compound 20.2g (0.98mmol), 4-
(1.07mmol), 8mL absolute methanols are placed in pressure tube (tube sealing), temperature be 85 DEG C, supersonic frequency 40kHz, ultrasound
Reaction filters after cooling to complete (TLC tracing detections, about 2h), is washed, obtained with absolute ethyl alcohol under conditions of power is 500W
Compound n (faint yellow solid) 0.330g, yield 90.7%.
Compound n：Yields 90.7%,1H NMR(500MHz,DMSO-d6)δ13.10(s,1H),8.89(s,1H),
7.97 (s, 1H), 7.95 (s, 1H), 7.79 (d, J=8.6Hz, 1H), 7.70 (s, 2H), 7.43 (d, J=8.5Hz, 1H), 2.55
(s,3H)；13C NMR(126MHz,DMSO-d6)δ146.54,146.06,141.35,138.40,134.84,132.19,
131.97,129.13,127.94,127.64,126.78,124.35,21.62.MS m/z:372[M+H]+.
Accordingly, it can be determined that above compound n is the chloro- 3- of 2- (the bromo- 1H- benzimidazolyl-2 radicals-yls of 5-) -6- methylquinolines,
Structural formula is shown below：
Embodiment 15：The chloro- 3- of 2- (the bromo- 1H- benzimidazolyl-2 radicals-yls of 5-) -6- methoxy quinolines (preparation of compound o)
With reference to the method for embodiment 1, bromo- 1, the 2- o-phenylenediamines 0.19g of Weigh Compound 30.2g (0.90mmol), 4-
(0.99mmol), 6mL n,N-dimethylacetamide are placed in pressure tube (tube sealing), are stirred to react to complete under the conditions of 80 DEG C
(TLC tracing detections, about 8h) entirely filters after cooling, is washed with absolute ethyl alcohol, obtain compound o (faint yellow solid) 0.199g,
Yield 57.1%.
Compound o：Yields 57.1%,1H NMR(500MHz,DMSO-d6)δ13.38(s,1H),8.88(s,1H),
7.98 (s, 1H), 7.90 (s, 1H), 7.67 (s, 1H), 7.61 (s, 1H), 7.58 (d, J=9.1Hz, 1H), 7.44 (d, J=
8.6Hz,1H),3.94(s,3H)；13C NMR(126MHz,DMSO-d6)δ158.77,149.55,144.67,143.48,
140.72,131.96,129.68,128.10,125.94,124.97,124.48,106.89,56.27.MS m/z:388[M+H
]+.
Accordingly, it can be determined that above compound o is the chloro- 3- of 2- (the bromo- 1H- benzimidazolyl-2 radicals-yls of 5-) -6- methoxy quinolines,
Its structural formula is shown below：
Embodiment 16：The chloro- 3- of 2- (the bromo- 1H- benzimidazolyl-2 radicals-yls of 5-)-[1,3] dioxolanes simultaneously (change by [6,7-g] quinoline
Close the preparation of object p)
With reference to the method for embodiment 3, bromo- 1, the 2- o-phenylenediamines 0.17g of Weigh Compound 40.2g (0.85mmol), 4-
(0.94mmol), 6mL absolute methanols are placed in pressure tube (tube sealing), temperature be 85 DEG C, supersonic frequency 40kHz, ultrasound
Reaction filters after cooling to complete (TLC tracing detections, about 2h), is washed, obtained with absolute ethyl alcohol under conditions of power is 240W
Compound p (faint yellow solid) 0.304g, yield 89.3%.
Compound p：Yields 89.3%,1H NMR(500MHz,DMSO-d6)δ12.67(s,1H),8.79(s,1H),
7.88 (s, 1H), 7.65 (d, J=8.6Hz, 1H), 7.56 (s, 1H), 7.44 (s, 1H), 7.42 (d, J=8.6Hz, 1H), 6.31
(s,2H)；13C NMR(126MHz,DMSO-d6)δ153.23,149.64,149.20,146.28,144.88,140.39,
131.96,129.12,125.87,124.10,121.99,115.15,104.58,103.55,103.30.MS m/z:402[M+
H]+.
Accordingly, it can be determined that above compound p is the chloro- 3- of 2- (the bromo- 1H- benzimidazolyl-2 radicals-yls of 5-)-[1,3] dioxolanes
And [6,7-g] quinoline, structural formula are shown below：
Embodiment 17：The chloro- 3- of 2- (the fluoro- 1H- benzimidazolyl-2 radicals-yls of 5-)-quinoline (preparation of compound q)
With reference to the method for embodiment 1, fluoro- 1, the 2- o-phenylenediamines 0.15g of Weigh Compound 10.2g (1.05mmol), 4-
(1.15mmol), 5mL absolute methanols and 2mL n,N-Dimethylformamide are placed in pressure tube (tube sealing), under the conditions of 80 DEG C
It is stirred to react to complete (TLC tracing detections, about 8h), is filtered after cooling, washed with absolute ethyl alcohol, it is (faint yellow to obtain compound q
Solid) 0.179g, yield 57.3%.
Compound q：Yields 57.3%,1H NMR(500MHz,DMSO-d6)δ13.08(s,1H),9.01(s,1H),
8.20 (d, J=7.6Hz, 1H), 8.07 (d, J=8.5Hz, 1H), 7.95 (d, J=8.4Hz, 1H), 7.77 (s, 1H), 7.70
(s, 1H), 7.50 (s, 1H), 7.16 (d, J=8.5Hz, 1H)；13C NMR(126MHz,DMSO-d6)δ147.48,147.36,
141.99,132.66,129.11,128.58,128.19,126.79,124.57.MS m/z:298[M+H]+.
Accordingly, it can be determined that above compound q is the chloro- 3- of 2- (the fluoro- 1H- benzimidazolyl-2 radicals-yls of 5-)-quinoline, structural formula
It is shown below：
Embodiment 18：The chloro- 3- of 2- (the fluoro- 1H- benzimidazolyl-2 radicals-yls of 5-) -6- methylquinolines (preparation of compound r)
With reference to the method for embodiment 3, fluoro- 1, the 2- o-phenylenediamines 0.14g of Weigh Compound 20.2g (0.98mmol), 4-
(1.07mmol), 7mL toluene are placed in pressure tube (tube sealing), temperature be 85 DEG C, supersonic frequency 45kHz, ultrasonic power
For reaction under conditions of 300W to complete (TLC tracing detections, about 2h), is filtered after cooling, washed with absolute ethyl alcohol, obtain chemical combination
Object r (faint yellow solid) 0.278g, yield 91.2%.
Compound r：Yields 91.2%,1H NMR(500MHz,DMSO-d6)δ13.01(s,1H),8.88(s,1H),
7.97 (d, J=8.6Hz, 1H), 7.78 (d, J=8.6Hz, 1H), 7.69 (s, 1H), 7.62 (s, 1H), 7.50 (d, J=
9.4Hz, 1H), 7.16 (d, J=8.8Hz, 1H), 2.55 (s, 3H)；13C NMR(126MHz,DMSO-d6)δ158.39,
149.59,146.57,146.03,141.23,138.37,134.78,133.54,127.94,127.61,126.79,124.46,
111.22,21.62.MS m/z:312[M+H]+.
Accordingly, it can be determined that above compound r is the chloro- 3- of 2- (the fluoro- 1H- benzimidazolyl-2 radicals-yls of 5-) -6- methylquinolines,
Structural formula is shown below：
Embodiment 19：The chloro- 3- of 2- (the fluoro- 1H- benzimidazolyl-2 radicals-yls of 5-) -6- methoxy quinolines (preparation of compound s)
With reference to the method for embodiment 1, fluoro- 1, the 2- o-phenylenediamines 0.13g of Weigh Compound 30.2g (0.90mmol), 4-
(0.99mmol), 6mL absolute methanols are placed in pressure tube (tube sealing), are stirred to react under the conditions of 80 DEG C to (TLC is tracked completely
Detection, about 8h), it is filtered after cooling, is washed with absolute ethyl alcohol, obtain compound s (faint yellow solid) 0.166g, yield
56.4%.
Compound s：Yields 56.4%,1H NMR(500MHz,DMSO-d6)δ13.04(s,1H),8.87(s,1H),
7.98 (d, J=9.2Hz, 1H), 7.71 (s, 1H), 7.61 (s, 1H), 7.56 (s, 1H), 7.43 (d, J=9.0Hz, 1H), 7.16
(s,1H),3.94(s,3H)；13C NMR(126MHz,DMSO-d6)δ158.75,140.51,132.03,129.68,128.13,
124.93,113.13,106.87,56.27.MS m/z:328[M+H]+.
Accordingly, it can be determined that above compound s is the chloro- 3- of 2- (the fluoro- 1H- benzimidazolyl-2 radicals-yls of 5-) -6- methoxy quinolines,
Its structural formula is shown below：
Embodiment 20：The chloro- 3- of 2- (the fluoro- 1H- benzimidazolyl-2 radicals-yls of 5-)-[1,3] dioxolanes simultaneously (change by [6,7-g] quinoline
Close the preparation of object t)
With reference to the method for embodiment 3, fluoro- 1, the 2- o-phenylenediamines 0.12g of Weigh Compound 40.2g (0.85mmol), 4-
(0.94mmol), 6mL normal propyl alcohols are placed in pressure tube (tube sealing), temperature be 75 DEG C, supersonic frequency 40kHz, ultrasonic work(
Reaction filters after cooling to complete (TLC tracing detections, about 2h), is washed, changed with absolute ethyl alcohol under conditions of rate is 450W
Close object t (faint yellow solid) 0.260g, yield 89.6%.
Compound t：Yields 89.6%,1H NMR(500MHz,DMSO-d6)δ12.91(s,1H),8.78(s,1H),
7.68 (d, J=8.8Hz, 1H), 7.55 (s, 1H), 7.48 (d, J=7.2Hz, 1H), 7.44 (s, 1H), 7.16 (s, 1H), 6.31
(s,2H)；13C NMR(126MHz,DMSO-d6)δ153.14,149.15,146.18,144.90,140.25,124.11,
122.21,104.55,103.52,103.26.MS m/z:342[M+H]+.
Accordingly, it can be determined that above compound t is the chloro- 3- of 2- (the fluoro- 1H- benzimidazolyl-2 radicals-yls of 5-)-[1,3] dioxolanes
And [6,7-g] quinoline, structural formula are shown below：
Embodiment 21：The chloro- 3- of 2- (the chloro- 1H- benzimidazolyl-2 radicals-yls of 5-)-quinoline (preparation of compound u)
With reference to the method for embodiment 1, chloro- 1, the 2- o-phenylenediamines 0.16g of Weigh Compound 10.2g (1.05mmol), 4-
(1.15mmol), 6mL absolute methanols are placed in pressure tube (tube sealing), are stirred to react under the conditions of 80 DEG C to (TLC is tracked completely
Detection, about 9h), it is filtered after cooling, is washed with absolute ethyl alcohol, obtain compound u (faint yellow solid) 0.187g, yield
56.9%.
Compound u：Yields 56.9%,1H NMR(500MHz,DMSO-d6)δ13.15(s,1H),9.02(s,1H),
8.21 (s, 1H), 8.08 (d, J=8.4Hz, 1H), 7.95 (s, 1H), 7.78 (d, J=8.1Hz, 1H), 7.76 (s, 1H), 7.72
(d, J=8.3Hz, 1H), 7.32 (d, J=8.6Hz, 1H)；13C NMR(126MHz,DMSO-d6)δ149.58,147.44,
147.41,142.09,132.70,129.12,128.58,128.19,126.76,124.41.MS m/z:314[M+H]+.
Accordingly, it can be determined that above compound u is the chloro- 3- of 2- (the chloro- 1H- benzimidazolyl-2 radicals-yls of 5-)-quinoline, structural formula
It is shown below：
Embodiment 22：The chloro- 3- of 2- (the chloro- 1H- benzimidazolyl-2 radicals-yls of 5-) -6- methylquinolines (preparation of compound v)
With reference to the method for embodiment 3, chloro- 1, the 2- o-phenylenediamines 0.15g of Weigh Compound 20.2g (0.98mmol), 4-
(1.07mmol), 6mL absolute methanols are placed in pressure tube (tube sealing), temperature be 85 DEG C, supersonic frequency 55kHz, ultrasound
Reaction filters after cooling to complete (TLC tracing detections, about 2h), is washed, obtained with absolute ethyl alcohol under conditions of power is 520W
Compound v (faint yellow solid) 0.291g, yield 90.9%.
Compound v：Yields 90.9%,1H NMR(500MHz,DMSO-d6)δ13.16(s,1H),8.88(s,1H),
7.97 (s, 1H), 7.95 (s, 1H), 7.78 (d, J=8.7Hz, 1H), 7.73 (s, 2H), 7.32 (d, J=8.6Hz, 1H), 2.55
(s,3H)；13C NMR(126MHz,DMSO-d6)δ149.69,146.53,146.05,141.31,138.37,134.81,
129.11,127.92,127.62,126.76,124.36,123.29,21.61.MS m/z:328[M+H]+.
Accordingly, it can be determined that above compound v is the chloro- 3- of 2- (the chloro- 1H- benzimidazolyl-2 radicals-yls of 5-) -6- methylquinolines,
Structural formula is shown below：
Embodiment 23：The chloro- 3- of 2- (the chloro- 1H- benzimidazolyl-2 radicals-yls of 5-) -6- methoxy quinolines (preparation of compound w)
With reference to the method for embodiment 1, chloro- 1, the 2- o-phenylenediamines 0.14g of Weigh Compound 30.2g (0.90mmol), 4-
(0.99mmol), 6mL absolute methanols are placed in pressure tube (tube sealing), are stirred to react under the conditions of 80 DEG C to (TLC is tracked completely
Detection, about 9h), it is filtered after cooling, is washed with absolute ethyl alcohol, obtain compound w (faint yellow solid) 0.170g, yield
55.1%.
Compound w：Yields 55.1%,1H NMR(500MHz,DMSO-d6)δ13.16(s,1H),8.88(s,1H),
7.98 (s, 1H), 7.76 (s, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.58 (d, J=9.1Hz, 1H), 7.32 (d, J=
8.6Hz,1H),3.94(s,3H)；13C NMR(126MHz,DMSO-d6)δ158.77,158.74,149.71,144.65,
143.46,140.73,129.68,128.10,127.38,125.01,124.47,123.35,106.89,56.26.MS m/z:
344[M+H]+.
Accordingly, it can be determined that above compound w is the chloro- 3- of 2- (the chloro- 1H- benzimidazolyl-2 radicals-yls of 5-) -6- methoxy quinolines,
Its structural formula is shown below：
Embodiment 24：The chloro- 3- of 2- (the chloro- 1H- benzimidazolyl-2 radicals-yls of 5-)-[1,3] dioxolanes simultaneously (change by [6,7-g] quinoline
Close the preparation of object x)
With reference to the method for embodiment 3, chloro- 1, the 2- o-phenylenediamines 0.13g of Weigh Compound 40.2g (0.85mmol), 4-
(0.94mmol), 6mL absolute methanols are placed in pressure tube (tube sealing), temperature be 50 DEG C, supersonic frequency 40kHz, ultrasound
Reaction filters after cooling to complete (TLC tracing detections, about 2h), is washed with water, obtains compound under conditions of power is 350W
X (faint yellow solid) 0.269g, yield 88.5%.
Compound x：Yields 88.5%,1H NMR(500MHz,DMSO-d6)δ13.15(s,1H),8.79(s,1H),
7.73 (s, 1H), 7.68 (d, J=8.7Hz, 1H), 7.55 (s, 1H), 7.44 (s, 1H), 7.30 (d, J=8.6Hz, 1H), 6.30
(s,2H)；13C NMR(126MHz,DMSO-d6)δ153.20,149.83,149.18,146.26,144.90,140.35,
137.28,124.11,123.21,122.10,121.74,116.79,116.31,114.16,104.56,103.28.MS m/z:
358[M+H]+.
Accordingly, it can be determined that above compound x is the chloro- 3- of 2- (the chloro- 1H- benzimidazolyl-2 radicals-yls of 5-)-[1,3] dioxolanes
And [6,7-g] quinoline, structural formula are shown below：
The antitumor action of the chloro- 3- of the 2- (1H- benzimidazolyl-2 radicals-yl)-quinoline to illustrate the invention, application
People is to the antitumor activity that compound has carried out made from above-mentioned raw materials compound 1,2,3 and 4 and above-described embodiment 1~24
Experiment (with common antitumor drug 5 FU 5 fluorouracil (5-FU) and cis-platinum (Cis-platin) for reference), and to above-described embodiment
Chemical combination obtained carries out the toxicity test to normal cell.
One, the anti tumor activity in vitro test of compound
1. the inoculation and culture of cell
Selected cell strain is placed in 37 DEG C, 5%CO2In incubator under the conditions of abundant humidifying, it is inoculated in containing 10% inactivation
It is cultivated in the PPMI1640 culture solutions of newborn bovine serum.Cell growth status is observed with inverted microscope, is replaced 2~3 times weekly
Culture medium, passage in 6~7 days is primary, and when inoculation is passed on 0.25% trypsin digestion, usually takes passage 3~4 times, in pair
Number growth period, cell was for testing.
2. the active primary dcreening operation of Compound cellular level
All compounds are configured to 100 μ g/mL, cosolvent by compound used in this experiment, purity >=95%
DMSO final concentrations are no more than 1%, and testing each compound under the concentration, to the inhibiting rate of cancer cell, all inhibiting rates are more than 50% and accord with
(such as cell shrinkage, the broken, floating) of suppressed (or impaired) metamorphosis of cell under closing light mirror, and not to normal cell toxicity
It is prodigious compound, then preliminary judgement is that the compound primary dcreening operation is effective, i.e., seeks IC into next step50Stage.
3. cell growth inhibition test (mtt assay)
MTT colorimetric methods are a kind of methods of detection cell growth and survival.Testing principle：It is different from dead cell, it is exogenous
MTT can be reduced to the bluish violet crystallization first a ceremonial jade-ladle, used in libation (Formazan) of water-insoluble simultaneously by the succinate dehydrogenase in living cells mitochondria
It is deposited in cell.Dimethyl sulfoxide (DMSO) (DMSO) can dissolve the first a ceremonial jade-ladle, used in libation in cell, with enzyme-linked immunosorbent assay instrument in 490nm wavelength
Place measures its absorbance value, can reflect living cells quantity indirectly.Within the scope of certain cell number, MTT crystallize the amount to be formed with it is thin
Born of the same parents' number is directly proportional.This method be widely used in the Activity determinations of some bioactie agents, large-scale screening anti-tumor medicine,
Cell toxicity test and tumor radiosensitivity measure etc., have the characteristics that high sensitivity, economic.
The cell in exponential phase is taken, per 180 μ L of hole (about 4500-5000 cell) celliferous culture medium inoculated
In 96 well culture plates, in 37 DEG C, 5%CO2It is cultivated for 24 hours under the conditions of abundant humidifying.After cell is adherent, add by the amount of 20 μ L of every hole
Enter sample, each sample sets 6 multiple holes, concurrently sets corresponding blank control.Continue after cultivating 48h, 10 μ L are added per hole
MTT reagents (a concentration of 5mg/mL) continue after being incubated 4h, and supernatant is abandoned in suction, and 150 μ L DMSO are added per hole, and slight concussion is anti-
5~8min is answered, crystalline particle is made fully to dissolve.Blank control group returns to zero, and removal bias light is measured with 490nm wavelength with microplate reader
Absorbance value after absorption valueCalculating cell proliferation inhibition rate, the test-compound good to primary dcreening operation antitumous effect, after
The continuous IC for being continued to do corresponding cell strain with 5 concentration gradients50Value, all experiments are averaged after being repeated 3 times.Experimental result is detailed
It see the table below 1.
Semi-inhibit rate concentration (IC of 1. compound of table to different tumor cell lines50, μM)
By data in table 1 it is found that in the inhibitory activity test experiments to human liver cancer cell HepG2, compound c, e, g,
I, k, m, o, u, w show good inhibitory activity, activity is significantly better than tumor Drugs 5-FU, wherein compound c, i
Activity is even better than clinical anti-cancer drugs Cisplatin, and they to the toxicity of people's normal cell lines of human liver HL-7702 significantly less than cis-platinum and
5-FU；In the inhibitory activity test experiments to Proliferation of Human Ovarian Cell SKOV-3, compound c, i, k, u, w show good suppression
System activity, activity are significantly better than tumor Drugs 5-FU, and it is suitable that the activity of wherein compound u, w is even better than clinical anti-cancer drug
Platinum, and they to the toxicity of people's normal cell lines of human liver HL-7702 significantly less than cis-platinum a and 5-FU；To human large cell lung cancer cell
In the inhibitory activity test experiments of NCI-H460, compound c, e, g, i, k, m, o, u, w show good inhibitory activity, activity
It is significantly better than tumor Drugs 5-FU, the activity of wherein compound c, i is even better than clinical anti-cancer drugs Cisplatin, and they are right
The toxicity of people's normal cell lines of human liver HL-7702 is significantly less than cis-platinum and 5-FU；In the inhibitory activity to human liver cancer cell BEL-7404
In test experiments, compound a and 5-FU；In the inhibitory activity test experiments to human large cell lung cancer cell NCI-H460, change
It closes object a, c, g, i, k, m, o, u, w and shows good inhibitory activity, activity is significantly better than tumor Drugs 5-FU, wherein changing
The activity for closing object o is even better than clinical anti-cancer drugs Cisplatin, and they to the toxicity of people's normal cell lines of human liver HL-7702 significantly less than
Cis-platinum and 5-FU.Especially it is worth noting that, all compounds are significantly better than the toxicity of people's normal cell lines of human liver HL-7702 anti-swollen
Tumor medicine 5-FU and cis-platinum.The above result shows that by the way that benzimidazole functional group introducing chinoline backbone is prepared novel 2-
Chloro- 3- (1H- benzimidazolyl-2 radicals-yl)-quinoline antitumoral compounds are feasible, can filter out the new antitumoral of high-efficiency low-toxicity
Compound, compared with common antitumor drug 5-FU and cis-platinum, the certain chloro- 3- of 2- (1H- benzimidazolyl-2 radicals-yl)-quinoline spread out
The activity of biology is more efficient, lower to the toxicity of normal cell.
Claims (10)
1. compound or its pharmaceutically acceptable salt shown in lower formula (I)：
Wherein,
R1For hydrogen or methoxyl group；
R2For hydrogen；
R3For methoxyl group, chloro or bromo；
R4For hydrogen or chloro.
2. the preparation method of compound described in claim 1, it is characterised in that：Take the institute of compound and formula (III) shown in formula (II)
Show that compound is dissolved in organic solvent, is reacted under heating condition to get to target product；
Wherein,
R1For hydrogen or methoxyl group；
R2For hydrogen；
R3For methoxyl group, chloro or bromo；
R4For hydrogen or chloro.
3. preparation method according to claim 2, it is characterised in that：The organic solvent is alcohols solvent and/or non-
Proton polar solvent.
4. preparation method according to claim 3, it is characterised in that：The alcohols solvent can be selected from volumetric concentration
For 80~100% methanol, volumetric concentration be 80~100% one or more of ethyl alcohol, normal propyl alcohol and n-butanol
Combination.
5. preparation method according to claim 3, it is characterised in that：The aprotic polar solvent is selected from N, N- bis-
The group of one or more of methylformamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide (DMSO), tetrahydrofuran and toluene
It closes.
6. preparation method according to claim 2, it is characterised in that：The organic solvent is ethylene glycol monomethyl ether.
7. the preparation method according to any one of claim 2~6, it is characterised in that：The reaction is extremely organic at 50 DEG C
It is carried out in the boiling point temperature range of solvent.
8. the preparation method according to any one of claim 2~6, it is characterised in that：The reaction is under ultrasound condition
It carries out.
9. compound described in claim 1 or its pharmaceutically acceptable salt application in preparation of anti-tumor drugs.
10. the antitumor drug prepared as active ingredient using compound described in claim 1 or its pharmaceutically acceptable salt.
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| US6479512B1 (en) * | 1999-10-19 | 2002-11-12 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
Non-Patent Citations (6)
| Title |
|---|
| 4-Hydroxy-2-Quinolones. 32.* Synthesis and Antithyroid Activity of Thio Anologs of 1H-2-Oxo-3-(2-Benzimidazolyl)-4-Hydroxyquinoline;I.V.Ukrainets et al.;《Chemistry of Heterocyclic Compounds》;19971231;第33卷(第5期);600-604 * |
| Novel Formation of 11,12-Dihydro-6H-Quino[2,3-b][1,5]benzodiazepines: Reaction of 2-Chloroquinoline-3-carbaldehydes with o-Phenylenediamine;Nanduri Bhanumathi et al.;《Heterocycles》;19861231;第24卷(第6期);1683-1685 * |
| RN 1023516-61-1;CAS;《STN REGISTRY》;20080529 * |
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| RN 1263357-12-5;CAS;《STN REGISTRY》;20110221 * |
| Synthesis of Novel Quino[2,3-b][1,5]benzodiazepin-12-ones;K. Rama Rao et al.;《Journal of Heterocyclic Chemistry》;19911231;第28卷(第5期);1339-1340 * |
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