CN108078992A - Pivaloyl amino dimethoxy benzo [d] azepine * bases quinazoline compounds are preparing the application in treating leukemia medicament - Google Patents
Pivaloyl amino dimethoxy benzo [d] azepine * bases quinazoline compounds are preparing the application in treating leukemia medicament Download PDFInfo
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Abstract
The invention discloses a kind of pivaloyl amino dimethoxy benzo [d] azepines
Description
(1) technical field
The present invention relates to a kind of application of quinazoline compounds, more particularly to a kind of pivaloyl amino dimethoxy benzo
[d] azepineApplication of the base quinazoline compounds in prevention or treatment human leukemia drug is prepared.
(2) background technology
Quinazoline compounds have many preferable bioactivity, have a wide range of applications in field of medicaments, and especially one
The quinazoline derivative of a little special constructions has apparent antiviral activity, antibacterial activity, antitumor activity etc., quinazoline ditosylate salt
Compound has had listed some kinds as antitumor drug.Such as the Gefitinib for being used to treat lung cancer of listing
(Gefitinib) and Tarceva (Erlotinib) and for treating the Lapatinib of breast cancer (Lapatinib), they
Belong to quinazoline compounds.Also common document report (refers to Y.- for new quinazoline compounds and its bioactivity
Y.Ke,H.-Y.Shiao,Y.C.Hsu,C.-Y.Chu,W.-C.Wang,Y.-C.Lee,W.-H.Lin,C.-H.Chen,
J.T.A.Hsu,C.-W.Chang,C.-W.Lin,T.-K.Yeh,Y.-S.Chao,M.S.Coumar,H.-P.Hsieh,
ChemMedChem 2013,8,136-148；A.Garofalo,A.Farce,S.Ravez,A.Lemoine,P.Six,
P.Chavatte,L.Goossens,P.Depreux,J.Med.Chem.2012,55,1189-1204).Certainly majority quinazoline
Class compound does not simultaneously have antitumor activity.
(3) content of the invention
It is an object of the invention to provide a kind of novel quinazoline quinoline class compound-pivaloyl amino dimethoxy benzos [d]
AzepineThe application of base quinazoline compounds, such compound is under doses to people in loop strain HL-
60 have good inhibition；And such compounds process for production thereof is easy, easily operated, raw material is easy to get, and production cost compared with
It is low, suitable for industrial applications.
For achieving the above object, the present invention adopts the following technical scheme that：
The present invention provides pivaloyl amino dimethoxy benzo [d] azepines shown in a kind of formula (I)Base quinazoline ditosylate salt
Application of the compound in prevention or tumor is prepared, particularly in prevention or treatment human leukemia drug is prepared
Using：
Preferably, the drug is with the drug for inhibiting people in loop strain HL-60 activity.
In addition, the present invention provides pivaloyl amino dimethoxy benzo [d] azepine shown in a kind of formula (I)Base quinazoline
The preparation method of class compound, the method are：(1) compound shown in formula (II) is mixed with compound shown in formula (III),
In organic solvent A, under the action of basic catalyst B, 25~120 DEG C are reacted that (TLC tracking and monitorings, solvent are second
Acetoacetic ester/petroleum ether=1：3 (v/v), preferably 40~100 DEG C 0.5~12h of reaction), after the reaction was complete, reaction solution is separated pure
Change, compound shown in formula (IV) is made；The organic solvent A is selected from one of following：It is chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, different
Propyl alcohol, acetonitrile or N,N-dimethylformamide；The basic catalyst B is selected from one of following：Pyridine, diethylamine, triethylamine,
Quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrollidinopyridines or sodium carbonate (preferably pyridine, diethylamine, three second
Amine, N, N- dimethylanilines or 4-dimethylaminopyridine)；
(2) formula (IV) compound represented under reducing agent E effects, has been reacted in organic solvent D at 25~100 DEG C
(TLC tracking and monitorings, solvent are ethyl acetate/petroleum ether=1 entirely：1 (v/v), preferably 40~80 DEG C 0.5~12h of reaction), instead
Liquid is answered to filter, formula (V) compound represented is made in the concentrate drying (preferably 25 DEG C vacuum drying) after filtrate decompression concentration；
The organic solvent D is one of following：Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N, N- dimethyl formyl
Amine；The reducing agent E is one of following：Iron powder/concentrated hydrochloric acid, iron powder/acetic acid, palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate；It is described
Iron powder/concentrated hydrochloric acid refers to that the mixing of iron powder and concentrated hydrochloric acid arbitrary proportion, iron powder/acetic acid refer to the mixed of iron powder and acetic acid arbitrary proportion
It closes, the palladium carbon/ammonium formate refers to the mixing of palladium carbon and ammonium formate arbitrary proportion, and the palladium carbon/hydrazine hydrate is palladium carbon and hydration
The mixture of hydrazine arbitrary proportion；
(3) compound shown in formula (V) is mixed with pivaloyl chloride or pivalic acid acid anhydride, under basic catalyst F effects, in
In organic solvent G, -10~50 DEG C the reaction was complete, and (TLC tracking and monitorings, solvent are ethyl acetate/petroleum ether=1：1 (v/v),
It is preferred that -10~50 DEG C of 3~12h of reaction), reaction solution is post-treated, and formula (I) compound represented is made；The base catalysis
Agent F is one of following：Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrrolidinyls
Pyridine or sodium carbonate；The organic solvent G is one of following：Tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, ether, second
Nitrile, toluene or benzene.
Further, in step (1), compound shown in compound shown in the formula (III) and formula (II), basic catalyst B
The ratio between the amount of substance of feeding intake is 1.0 ﹕, 0.8~1.2 ﹕ 1.0~8.0.
Further, in step (1), the dosage of the organic solvent A is calculated as 10 with the quality of compound shown in formula (III)~
50mL/g。
Further, the method that reaction solution isolates and purifies described in step (1) of the present invention is：After the reaction was complete, by reaction solution
Solvent is evaporated off, concentrate is taken to be dissolved with organic solvent C, obtain lysate, then into lysate add in concentrate 1.0~
After mixing, solvent is evaporated off in the column chromatography silica gel of 2.0 times of weight, dry, the mixture of concentrate and silica gel is obtained, by mixture
Column is filled, then using volume ratio as 1：0.1~10 petroleum ether is eluant, eluent with ethyl acetate mixture, is collected containing target components
Efflux (preferably with ethyl acetate/petroleum ether=1：3 (v/v) are solvent tracing detection, collect target components, preferably receive
Collect the component that Rf values are 0.5), it is concentrated under reduced pressure, dry (preferably 50 DEG C of dryings) obtain formula (IV) compound represented；It is described to have
Solvent C is one of following：Ethyl alcohol, chloroform, tetrahydrofuran or ethyl acetate.The organic solvent C dosages are so as to dissolving is residual
Stay object.
Further, in step (2), when the reducing agent E is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, formula (IV) institute
The mass ratio that feeds intake of iron powder, concentrated hydrochloric acid or acetic acid in the compound and reducing agent E shown is 1.0 ﹕, 1.0~3.0 ﹕ 0.2~1.0.
In the present invention, concentrated hydrochloric acid mass concentration is 36%~38%, and acetic acid uses glacial acetic acid.
Further, in step (2), when the reducing agent E is palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate, formula (IV) institute
The compound shown in reducing agent E palladium carbon, ammonium formate or hydrazine hydrate feed intake mass ratio for 1.0 ﹕, 0.1~0.5 ﹕ 1.0~
3.0.The mass loading amount of palladium is 2~10%, preferably 5% in the palladium carbon being applicable in the present invention, hydrazine hydrate mass concentration for 40~
80%, preferably 80%.
Further, in step (2), the dosage of the organic solvent D is calculated as 10 with the quality of formula (IV) compound represented
~50mL/g.
Further, in step (3), compound shown in the formula (V) and pivaloyl chloride or pivalic acid acid anhydride, base catalysis
The ratio between amount for the substance that feeds intake of agent F is 1 ﹕, 1.0~8.0 ﹕ 1.0~3.0.
Further, in step (3), the dosage of the organic solvent G is calculated as 11 with the quality of compound shown in formula (V)~
100mL/g。
Further, the specific recommendation step (3) of the present invention carries out as follows：Under the conditions of -10~10 DEG C, toward formula
(V) in the organic solvent G solution of compound shown in and basic catalyst F or toward compound and base catalysis shown in formula (V)
The organic solvent G solution of pivaloyl chloride or pivalic acid acid anhydride is added dropwise in agent F, drop finishes, and when -10~50 DEG C of reactions 3~12 are small, gained is anti-
Answer liquid is post-treated to obtain compound shown in formula (I)；The organic solvent volume dosage of pivaloyl chloride or pivalic acid acid anhydride is dissolved to this
Invention does not influence, and total dosage of the organic solvent G is calculated as 11~100mL/g with the quality of compound shown in formula (V).It is organic
Total dosage of solvent G refer to dissolve the organic solvent G of compound shown in basic catalyst F and formula (V) and dissolving pivaloyl chloride or
The total volume of pivalic acid acid anhydride organic solvent G.
Further, the method for step (3) the of the present invention reaction solution post processing is：After the reaction was complete, by reacting liquid filtering,
Filtrate steaming removal solvent takes concentrate to be dissolved with organic solvent H, obtains lysate, concentrate is then added in into lysate
After mixing, solvent is evaporated off in the column chromatography silica gel of 1.0~2.0 times of weight, dry, obtains the mixture of concentrate and silica gel, will be mixed
Object dress column is closed, then using volume ratio as 1：0.1~10 petroleum ether is eluant, eluent with ethyl acetate mixture, is collected containing target
The efflux of component is (preferably with ethyl acetate/petroleum ether=1：1 (v/v) is solvent tracing detection, collects target components), subtract
Pressure concentration, dry (preferably 50 DEG C of dryings) obtain formula (I) compound represented；The organic solvent H is one of following：Ethyl alcohol,
Chloroform, tetrahydrofuran or ethyl acetate.The organic solvent H dosages are so as to dissolution residual substance.
Organic solvent A of the present invention, C, D, G and H are organic solvent, organic used in different step for the ease of distinguishing
Solvent is different and names, and letter itself does not have meaning；The catalyst B, reducing agent E and catalyst F are catalyst, in order to just
It is named in differentiation different step used catalyst difference, letter itself does not have meaning.
The beneficial effects are mainly as follows：Provide a kind of new pivaloyl amino dimethoxy benzo [d]
AzepineApplication of the base quinazoline compounds (I) in prevention or treatment human leukemia drug is prepared, the compound are early to people
Young grain leukemia cell line HL-60 has significant inhibitory activity.
(4) specific embodiment
The present invention be further described in conjunction with specific embodiments, following embodiment illustrate the present invention rather than
It limit the invention in any way.
Compound (II) prepare reference literature (Weinstock, J.et al.J.Med.Chem., 1986,29 (11),
Method 2315-2325) is prepared.The chloro- 6- nitro-quinazolines (III) of 4- prepare reference literature (Fernandes, C.et
Al.Bioorg.Med.Chem., 2007,15 (12), 3974-3980) method be prepared.
Palladium carbon (Pd/C) model D5H5A that the embodiment of the present invention uses, is purchased from Shaanxi Ruike New Materials Co., Ltd..
Embodiment 1：Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 2.39 grams of (6.87mmol) compounds
(II), 3.62 grams of (45.76mmol) pyridines, 12 milliliters of chloroforms are added in 50 milliliters of reaction bulb, are heated to 40 DEG C, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：3 (v/v)), be stirred to react 10 it is small when, close reaction, reaction solution is evaporated off molten
Agent adds in 10 milliliters of ethyl acetate in obtained concentrate and is dissolved, obtains lysate, 3.0 grams of columns are added in into lysate
Chromatographic silica gel (300~400 mesh column chromatography silica gel) after mixing, is evaporated off solvent, obtains the mixture of dry concentrate and silica gel,
Mixture is filled into column, then using volume ratio as 1：10 petrol ether/ethyl acetate mixed solution is eluant, eluent, is eluted, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：3 (v/v)), it is collected according to TLC detections containing formula (IV) compound represented
Eluent (Rf values are 0.5), collection liquid concentration, 50 DEG C are dried to obtain the faint yellow solid product shown in formula (IV), yield
85.1%, 164~166 DEG C of fusing point.1H NMR(500MHz,CDCl3)δ:3.32-3.38 (m, 1H), 3.63 (dt, J=3.4,
15.5Hz, 1H), 3.75 (s, 3H), 3.82 (s, 6H), 3.91 (dd, J=8.1,14.3Hz, 1H), 4.03 (td, J=4.1,
11.7Hz, 1H), 4.15 (d, J=11.5Hz, 1H), 4.72 (dd, J=8.3,14.2Hz, 1H), 5.14 (t, J=8.9Hz,
1H), 6.60 (s, 1H), 6.90 (d, J=8.7Hz, 2H), 7.08 (d, J=8.6Hz, 2H), 7.93 (d, J=9.1Hz, 1H),
8.48 (dd, J=2.4,9.2Hz, 1H), 8.71 (s, 1H), 8.96 (d, J=2.4Hz, 1H).IR(KBr,cm-1)ν:2917,
2848,1616,1580,1510,1463,1355,1327,1249,1038,847。
Embodiment 2：Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.59 grams of (4.57mmol) compounds
(II), 1.67 grams of (22.83mmol) diethylamine, 60 milliliters of toluene are added in 100 milliliters of three-necked flask, are heated to 100 DEG C,
(solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), be stirred to react 2 it is small when, close reaction, reaction solution
Solvent is evaporated off, 20 milliliters of ethyl alcohol are added in obtained concentrate and are dissolved, obtain lysate, 2.5 grams are added in into lysate
Column chromatography silica gel (300~400 mesh column chromatography silica gel) after mixing, is evaporated off solvent, obtains the mixing of dry concentrate and silica gel
Mixture is filled column, then using volume ratio as 1 by object：5 petrol ether/ethyl acetate mixed solution be eluant, eluent, elution, TLC with
(solvent is ethyl acetate/petroleum ether=1 for track detection：3 (v/v)), it is collected according to TLC detections containing formula (IV) compound represented
Eluent (Rf values be 0.5), collection liquid concentration, 50 DEG C are dried to obtain the faint yellow solid product shown in formula (IV), yield
72.6%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 3：Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.99 grams of (5.72mmol) compounds
(II), 0.58 gram of (5.73mmol) triethylamine, 60 milliliters of ethyl alcohol are added in 100 milliliters of three-necked flask, are heated to 60 DEG C, TLC
(solvent is ethyl acetate/petroleum ether=1 to tracing detection：3 (v/v)), be stirred to react 8 it is small when, close reaction, reaction solution is evaporated off
Solvent adds in 20 milliliters of chloroforms in obtained concentrate and is dissolved, obtains lysate, 2.5 grams of column layers are added in into lysate
Silica gel (300~400 mesh column chromatography silica gel) is analysed, after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, it will
Mixture fills column, then using volume ratio as 10：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, and elution, TLC, which is tracked, to be examined
(solvent is ethyl acetate/petroleum ether=1 for survey：3 (v/v)), it is detected according to TLC and collects washing for (IV) compound represented Han formula
De- liquid (Rf values are 0.5), collection liquid concentrates, and 50 DEG C are dried to obtain the faint yellow solid product shown in formula (IV), yield 77.2%,
164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 4：Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 2.20 grams of (6.32mmol) compounds
(II), 1.40 grams of (11.46mmol) 4-dimethylaminopyridine, 60 milliliters of isopropanols are added in 100 milliliters of three-necked flask, room temperature
25 DEG C of stirrings, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), when reaction 12 is small, reaction is closed,
Solvent is evaporated off in reaction solution, and 20 milliliters of tetrahydrofurans are added in obtained concentrate and are dissolved, lysate are obtained, into lysate
4.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added in, after mixing, solvent is evaporated off, obtains dry concentrate and silicon
Mixture is filled column, then using volume ratio as 5 by the mixture of glue：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, is washed
De-, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), it is collected according to TLC detections containing shown in formula (IV)
Compound eluent (Rf values be 0.5), collection liquid concentration, 50 DEG C of faint yellow solids productions being dried to obtain shown in formula (IV)
Object, yield 80.2%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 5：Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.79 grams of (5.15mmol) compounds
(II), 1.04 grams of (8.58mmol) N, N- dimethylanilines, 12 milliliters of n,N-Dimethylformamide are added in 50 milliliters of reaction bulb,
120 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), be stirred to react 0.5 it is small when, close
Reaction is closed, solvent is evaporated off in reaction solution, and 20 milliliters of tetrahydrofurans are added in obtained concentrate and are dissolved, obtain lysate, to
5.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added in lysate, after mixing, solvent is evaporated off, are obtained dry dense
Mixture is filled column, then using volume ratio as 1 by the mixture of contracting object and silica gel：1 petrol ether/ethyl acetate mixed solution is
Eluant, eluent, elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), it is collected and contained according to TLC detections
The eluent (Rf values be 0.5) of formula (IV) compound represented, collection liquid concentration, 50 DEG C be dried to obtain it is yellowish shown in formula (IV)
Color solid product, yield 89.6%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 6：Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 2.39 grams of (6.87mmol) compounds
(II), 3.62 grams of (45.76mmol) pyridines, 20 milliliters of propyl alcohol are added in 50 milliliters of reaction bulb, are heated to 40 DEG C, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：3 (v/v)), be stirred to react 10 it is small when, close reaction, reaction solution is evaporated off molten
Agent adds in 20 milliliters of ethyl acetate in obtained concentrate and is dissolved, obtains lysate, 3.5 grams of columns are added in into lysate
Chromatographic silica gel (300~400 mesh column chromatography silica gel) after mixing, is evaporated off solvent, obtains the mixture of dry concentrate and silica gel,
Mixture is filled into column, then using volume ratio as 1：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, is eluted, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：3 (v/v)), it is collected according to TLC detections containing formula (IV) compound represented
Eluent (Rf values are 0.5), collection liquid concentration, 50 DEG C are dried to obtain the faint yellow solid product shown in formula (IV), yield
78.3%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 7：Amino benzo [d] azepineThe preparation of base quinazoline (V)
0.40 gram of (0.77mmol) nitro benzo [d] azepine successively prepared by 1 method of embodimentBase quinazoline (IV),
0.40 gram of (6.34mmol) ammonium formate, 0.04 gram of 5%Pd/C, 4.0 milliliters of chloroforms are added in reaction bulb, 25 DEG C of stirrings of room temperature,
(solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), when reaction 12 is small, filtering, filtrate concentration, 25 DEG C
Vacuum drying obtains faint yellow solid product amino benzo [d] azepineBase quinazoline (V), yield 98.2%, fusing point 122~
126℃。1H NMR(500MHz,CDCl3)δ:3.40-3.48(m,2H),3.71(s,3H),3.82(s,3H),3.83(s,3H),
3.87-3.98 (m, 5H), 4.45 (dd, J=6.3,13.8Hz, 1H), 4.95 (dd, J=6.5,9.2Hz, 1H), 6.47 (s,
1H), 6.90 (d, J=8.7Hz, 2H), 6.95 (d, J=2.5Hz, 1H), 7.11 (d, J=8.6Hz, 2H), 7.15 (dd, J=
8.9,2.5Hz, 1H), 7.69 (d, J=8.9Hz, 1H), 8.50 (s, 1H).IR(KBr,cm-1)ν:3368,3215,2932,
2825,1628,1566,1512,1487,1353,1248,1036,834。
Embodiment 8：Amino benzo [d] azepineThe preparation of base quinazoline (V)
0.40 gram of (0.77mmol) nitro benzo [d] azepine successively prepared by 2 method of embodimentBase quinazoline (IV),
1.20 grams of (19.18mmol) 80wt% hydrazine hydrates, 0.20 gram of 5%Pd/C, 20.0 milliliters of toluene are added to 50 milliliters of reaction bulb
In, 100 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is small to be stirred to react 0.5
When, cold filtration, filtrate concentrates, and 25 DEG C of vacuum drying obtain faint yellow solid product amino benzo [d] azepineBase quinazoline
(V), yield 100.0%, 122~126 DEG C of fusing point.1H NMR and IR is the same as embodiment 7.
Embodiment 9：Amino benzo [d] azepineThe preparation of base quinazoline (V)
0.40 gram of (0.77mmol) nitro benzo [d] azepine successively prepared by 3 method of embodimentBase quinazoline (IV),
0.08 gram of concentrated hydrochloric acid (mass concentration 36~38%), 0.40 gram of iron powder, 20.0 ml methanols are added in 50 milliliters of reaction bulb,
40 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), be stirred to react 8 it is small when, cooling
Filtering, filtrate concentration, 25 DEG C of vacuum drying obtain faint yellow solid product amino benzo [d] azepineBase quinazoline (V) is received
Rate 94.1%, 122~126 DEG C of fusing point.1H NMR and IR is the same as embodiment 7.
Embodiment 10：Amino benzo [d] azepineThe preparation of base quinazoline (V)
0.40 gram of (0.77mmol) nitro benzo [d] azepine successively prepared by 4 method of embodimentBase quinazoline (IV),
0.40 gram of acetic acid, 1.20 grams of iron powders, 20.0 milliliters of isopropanols are added in 50 milliliters of reaction bulb, are heated to 80 DEG C, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：1 (v/v)), be stirred to react 3 it is small when, cold filtration, filtrate concentration, 25 DEG C
Vacuum drying obtains faint yellow solid product amino benzo [d] azepineBase quinazoline (V), yield 97.5%, fusing point 122~
126℃。1H NMR and IR is the same as embodiment 7.
Embodiment 11：Pivaloyl amino dimethoxy benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 7 method of embodimentBase quinazoline (V),
0.13 gram of (1.64mmol) pyridine, 3 milliliters of tetrahydrofurans are added in reaction bulb, and 0.531 gram is added dropwise under -10 DEG C of stirring conditions
(4.40mmol) pivaloyl chloride, drop finish, and (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1), under the conditions of -10 DEG C
React 12 it is small when, filtering, filtrate steaming removal solvent, concentrate add in 10 milliliters of ethyl acetate dissolved, obtain lysate, Xiang Rong
It solves and 0.60 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added in liquid, after mixing, solvent is evaporated off, obtains dry concentration
Mixture is filled column, then using volume ratio as 1 by the mixture of object and silica gel：10 petrol ether/ethyl acetate mixed solution is to wash
De- agent, elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is collected according to TLC detections containing formula
(I) eluent (Rf values are 0.5) of compound represented, collection liquid concentration, 50 DEG C are dried to obtain the pivaloyl ammonia shown in formula (I)
Base dimethoxy benzo [d] azepineBase quinazoline pale solid, yield 64.2%, 131~133 DEG C of fusing point.1H NMR
(500MHz,[D6]DMSO)δ:1.29(s,9H),3.22-3.28(m,1H),3.38-3.42(m,1H),3.68(s,3H),3.69
(s, 3H), 3.73 (s, 3H), 3.78-3.84 (m, 1H), 3.87-3.96 (m, 2H), 4.49 (dd, J=8.2,14.7,1H),
5.26 (t, J=8.6Hz, 1H), 6.85 (s, 1H), 6.89 (d, J=8.8Hz, 2H), 7.08 (d, J=8.7Hz, 2H), 7.69
(d, J=9.0,1H), 7.88 (dd, J=2.2,9.2Hz, 1H), 8.44 (s, 1H), 8.66 (s, 1H), 9.55 (s, 1H).HRMS-
ESI m/z:575.2417[M+H]+。IR(KBr,cm-1)ν:2966,2921,2868,1665,1557,1522,1510,1490,
1163,1349,1248,1036,847。
Embodiment 12：Pivaloyl amino dimethoxy benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 8 method of embodimentBase quinazoline (V),
0.04 gram of (0.55mmol) diethylamine, 10.0 milliliters of chloroforms are added in 50 milliliters of reaction bulb, are added dropwise under 10 DEG C of stirring conditions
0.066 gram of (0.55mmol) pivaloyl chloride and 5.0 milliliters of chloroform mixed solutions, drop finish, and (solvent is acetic acid to TLC tracing detections
Ethyl ester/petroleum ether=1：1 (v/v)), when reaction 8 is small under the conditions of 10 DEG C, filtering, filtrate steaming removal solvent, concentrate adds in 20 milliliters
Ethyl alcohol is dissolved, and obtains lysate, and 0.26 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added in into lysate,
After mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then using volume ratio as 1：5
Petrol ether/ethyl acetate mixed solution is eluant, eluent, and elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1
(v/v)) eluent (Rf values are 0.5) containing formula (I) compound represented, is collected according to TLC detections, collection liquid concentrates, 50 DEG C
It is dried to obtain pivaloyl amino dimethoxy benzo [d] azepine shown in formula (I)Base quinazoline pale solid, yield
74.7%, 131~133 DEG C of fusing point.1H NMR and IR is the same as embodiment 11.
Embodiment 13：Pivaloyl amino dimethoxy benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 9 method of embodimentBase quinazoline (V),
0.111 gram of (1.10mmol) triethylamine, 10.0 milliliters of ethyl acetate are added in 50 milliliters of reaction bulb, under 0 DEG C of stirring condition
0.133 gram of (1.10mmol) pivaloyl chloride and 5.0 milliliters of ethyl acetate solutions are added dropwise, drop finishes, and (solvent is TLC tracing detections
Ethyl acetate/petroleum ether=1：1) when, reaction 6 is small under the conditions of 25 DEG C, filtering, filtrate steaming removal solvent, concentrate adds in 20 milliliters
Chloroform is dissolved, and obtains lysate, and 0.30 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added in into lysate,
After mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then using volume ratio as 10：1
Petrol ether/ethyl acetate mixed solution for eluant, eluent, elution, TLC tracing detections (solvent for ethyl acetate/petroleum ether=
1：1 (v/v)), the eluent (Rf values are 0.5) containing formula (I) compound represented is collected according to TLC detections, collection liquid concentrates, and 50
DEG C it is dried to obtain pivaloyl amino dimethoxy benzo [d] azepine shown in formula (I)Base quinazoline pale solid, yield
50.5%, 131~133 DEG C of fusing point.1H NMR and IR is the same as embodiment 11.
Embodiment 14：Pivaloyl amino dimethoxy benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 10 method of embodimentBase quinazoline
(V), 0.067 gram of (0.55mmol) 4-dimethylaminopyridine, 20.0 milliliters of toluene are added in 50 milliliters of reaction bulb, and 5 DEG C are stirred
The solution of 0.410 gram of (2.20mmol) pivalic acid acid anhydride and 7.0 milliliters of toluene is added dropwise under the conditions of mixing, drop finishes, and is heated to 50 DEG C, TLC
(solvent is ethyl acetate/petroleum ether=1 to tracing detection：1) when, reaction 3 is small, filtering, filtrate steaming removal solvent, concentrate addition
20 milliliters of tetrahydrofurans are dissolved, and obtain lysate, and 0.40 gram of column chromatography silica gel (300~400 mesh column is added in into lysate
Chromatographic silica gel), after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then with body
Product is than being 5：1 petrol ether/ethyl acetate mixed solution be eluant, eluent, elution, TLC tracing detections (solvent for ethyl acetate/
Petroleum ether=1：1 (v/v)), the eluent (Rf values are 0.5) containing formula (I) compound represented is collected according to TLC detections, is collected
Liquid concentrates, 50 DEG C of pivaloyl amino dimethoxy benzo [d] azepines being dried to obtain shown in formula (I)Base quinazoline canescence is consolidated
Body, 131~133 DEG C of 57.4% fusing point of yield.1H NMR and IR is the same as embodiment 11.
Embodiment 15：Pivaloyl amino dimethoxy benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 7 method of embodimentBase quinazoline (V),
0.213 gram of (1.65mmol) quinoline, 15.0 milliliters of benzene are added in 50 milliliters of reaction bulb, are added dropwise under -10 DEG C of stirring conditions
The solution of 0.265 gram of (2.20mmol) pivaloyl chloride and 5.0 milliliters of benzene, drop finish, TLC tracing detections (solvent for ethyl acetate/
Petroleum ether=1：1) when, reaction 12 is small under the conditions of -10 DEG C, filtering, filtrate steaming removal solvent, concentrate adds in 20 milliliters of tetrahydrofurans
It is dissolved, obtains lysate, 0.40 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel), mixing are added in into lysate
Afterwards, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then using volume ratio as 1：1 oil
Ether/ethyl acetate mixture is eluant, eluent, and elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1(v/
V)), the eluent (Rf values are 0.5) containing formula (I) compound represented, collection liquid concentration, 50 DEG C of dryings are collected according to TLC detections
Obtain pivaloyl amino dimethoxy benzo [d] azepine shown in formula (I)Base quinazoline pale solid, yield 70.9%,
131~133 DEG C of fusing point.1H NMR and IR is the same as embodiment 11.
Embodiment 16：Pivaloyl amino dimethoxy benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 7 method of embodimentBase quinazoline (V),
0.164 gram of (1.10mmol) 4- pyrollidinopyridine, 15.0 milliliters of dichloromethane are added in 50 milliliters of reaction bulb, and 10 DEG C are stirred
0.133 gram of (1.10mmol) pivaloyl chloride and 5.0 milliliters of dichloromethane solutions are added dropwise under the conditions of mixing, drop finishes, TLC tracing detections
(solvent is ethyl acetate/petroleum ether=1：1) when, reaction 8 is small under the conditions of 10 DEG C, filtering, filtrate steaming removal solvent, concentrate adds
Enter 20 milliliters of ethyl alcohol to be dissolved, obtain lysate, 0.50 gram of column chromatography silica gel (300~400 mesh column layer is added in into lysate
Analyse silica gel), after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then with volume
Than for 10：1 petrol ether/ethyl acetate mixed solution be eluant, eluent, elution, TLC tracing detections (solvent for ethyl acetate/
Petroleum ether=1：1 (v/v)), the eluent (Rf values are 0.5) containing formula (I) compound represented is collected according to TLC detections, is collected
Liquid concentrates, 50 DEG C of pivaloyl amino dimethoxy benzo [d] azepines being dried to obtain shown in formula (I)Base quinazoline canescence is consolidated
Body, yield 68.6%, 131~133 DEG C of fusing point.1H NMR and IR is the same as embodiment 11.
Embodiment 17：Active anticancer testing in vitro
(1) compound obtained (I) people in loop strain HL-60 biological activity tests have been subjected to.
Test method：Tetrazolium reduction method (mtt assay).
Cell line：People in loop strain HL-60.Above-mentioned tumor cell line is purchased from Chinese Academy of Sciences's Shanghai life
Academy of sciences's cell bank.
Experimental procedure is as follows：
(a) preparation of sample：For solvable sample, dissolved per 1mg with 40 μ L DMSO, take 2 μ L dilute with 1000 μ L culture mediums
It releases, makes concentration for 100 μ g/mL, then with culture solution serial dilution to concentration.
(b) culture of cell
1. the preparation of culture medium:Containing 800,000 units of Penicillin, 1.0g strepto-s in per 1000mL DMEM culture mediums (Gibco)
Element, 10% inactivated fetal bovine serum.
2. the culture of cell：By tumor cell inoculation in culture medium, 37 DEG C are put, 5%CO2It is cultivated in incubator, 3~5d
Passage.
3. determination sample is to the inhibitory action of growth of tumour cell
2nd generation cell EDTA- pancreatin digestive juice is digested, and 1 × 10 is diluted to culture medium6It is thin to be added to 96 holes by/mL
In born of the same parents' culture plate, per 100 μ L of hole, 37 DEG C are put, 5%CO2It is cultivated in incubator.After inoculation for 24 hours, it is separately added into and is diluted with culture medium
100 μ g/mL, 10 μ g/mL and 1 μ g/mL samples, per 100 μ L of hole, each concentration adds 3 holes, puts 37 DEG C, 5%CO2In incubator
It cultivates, adds in the MTT of 5mg/mL after 72h in cell culture well, per 10 μ L of hole, put 37 DEG C of incubation 3h, add in DMSO, every hole
150 μ L, are vibrated with oscillator, and Shi Jia Za is completely dissolved, with microplate reader under 570nm wavelength colorimetric.To be free of under similarity condition
Sample, the cell of the medium culture containing similary concentration DMSO calculate IC of the sample to growth of tumour cell as control50。
The results are shown in Table 1 for test：
The inhibitory action that 1. compound of table (I) grows cancer cell line HL-60
(2) according to embodiment 11, pivaloyl chloride is replaced respectively with 3- methoxy benzoyl chlorides or cinnamoyl chloride, other behaviour
Make with embodiment 11, be respectively synthesized quinazoline compounds (b) and (c), structure is as follows：
Quinazoline compounds (b) obtained and (c) have been carried out by people in loop strain according to the above method
HL-60 biological activity tests, test result show quinazoline compounds (b) and (c) to people in loop strain HL-
The equal unobvious of 60 inhibitions, compound (b) and (c) can not show a candle to the active anticancer of people in loop strain HL-60
Compound (I).Concrete outcome is as shown in table 2：
The inhibitory action that 2. compound (b) of table and (c) grow cancer cell line HL-60
Above-mentioned active anticancer testing in vitro experiment shows：The similar compound (b) of other 2 structures and (c) are to the early children of people
The equal unobvious of inhibitory action of grain leukemia cell line HL-60 growth.Compound (I) is to people in loop strain HL-
The inhibitory action of 60 growths is notable, hence it is evident that better than compound (b) and (c).
(3) according to embodiment 11, pivaloyl chloride is replaced respectively with cyclohexyl methyl chloro-formate or propionyl chloride, other behaviour
Make with embodiment 11, be respectively synthesized quinazoline compounds (k) and (g), structure is as follows：
Quinazoline compounds (k) obtained and (g) have been carried out by people in loop strain according to the above method
HL-60 biological activity tests, test result show quinazoline compounds (k) and (g) to people in loop strain HL-
60 active anticancer is not so good as compound (I).Concrete outcome is as shown in table 3：
The inhibitory action that 3. compound (k) of table and (g) grow cancer cell line HL-60
Claims (2)
1. pivaloyl amino dimethoxy benzo [d] azepine as shown in formula (I)Base quinazoline compounds are preparing prevention
Or the application in treatment human leukemia drug；
2. application as described in claim 1, it is characterised in that the drug is with inhibition people in loop strain
The drug of HL-60 activity.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1061411A (en) * | 1990-11-06 | 1992-05-27 | 美国辉瑞有限公司 | Be used to strengthen the active quinazoline derivant of antineoplastic agent |
| WO1995023141A1 (en) * | 1994-02-23 | 1995-08-31 | Pfizer Inc. | 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1061411A (en) * | 1990-11-06 | 1992-05-27 | 美国辉瑞有限公司 | Be used to strengthen the active quinazoline derivant of antineoplastic agent |
| WO1995023141A1 (en) * | 1994-02-23 | 1995-08-31 | Pfizer Inc. | 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents |
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