CN103204818B - Preparation method of multi-substituted quinazoline derivative - Google Patents
Preparation method of multi-substituted quinazoline derivative Download PDFInfo
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Abstract
The invention discloses a preparation method of a multi-substituted quinazoline derivative and belongs to the technical field of pharmaceutical synthesis and chemical product synthesis. The preparation method comprises the following steps of: adding diaryl hyper-valent iodine salt and copper salt to a reactor; changing the nitrogen gas by three times and adding a solvent; adding nitrile by two steps; heating up until the reaction is finished after the adding is finished; cooling the reaction system, adding water or a salt solution for quenching the reaction; adding dichloromethane and K2CO3 for stirring and treating; extracting by dichloromethane by three times; combining organic phases; adding magnesium sulfate for drying and filtering; evaporating and concentrating filtrate to obtain a crude product in a rotary manner; and separating the crude product by eluent to obtain the product. The preparation method of the multi-substituted quinazoline derivative has the beneficial effects that the preparation method is scientific and reasonable, capable of synthesizing the multi-substituted quinazoline derivative which is difficult to synthesize by other methods. Moreover, the synthesis method has the characteristics of being simple in structure, high in yield, easy for realization of products and the like.
Description
Technical field
The invention belongs to pharmaceutical synthesis and Chemicals synthesis technical field, particularly a kind of preparation method of polysubstituted quinazoline derivant.
Background technology
Quinazoline compounds shows good biological activity in medicine and agricultural chemicals, is one of focus of region of chemistry and organic sphere research.In medical, it produces restraining effect to EGF acceptor (EGFR), and shows antitumour activity.In addition, quinazoline compounds also has anti-malarial, antitumor and HIV (human immunodeficiency virus)-resistant activity; Also can be used for treatment benign prostatic hyperplasia and hypertrophy; As alpha-blocking agent, in the control of cardiovascular disorder, also occupy the effect of outbalance, such as, can the atherosis and coronary heart disease of prevention of arterial.Agricultural chemicals aspect, quinazoline compounds has obvious anti-microbial activity, resisting tobacco mosaic virus (TMV) activity and weeding activity.
The preparation method of quinazoline derivant has:
1) take anthranilic acid as raw material
(1) with formamide: anthranilic acid derivative becomes ring to form quinazoline female ring with formamide be the method extensively adopted.2006, Shao Haizhou etc. with 6-aminoveratric acid and methane amide for starting raw material, 6 have directly been synthesized through " one kettle way " under phosphorus oxychloride exists, 7-dimethoxy-4 '-chloro-quinazoline, be substituted and be obtained by reacting target compound, the reaction of this synthetic method is fast, and productive rate is high, easy and simple to handle, low in the pollution of the environment.
(2) react with acid anhydrides, aliphatic amide: Ines Nouira etc. and Ioannis K.Kostakis etc. are from anthranilic acid, through intermediate 1,3-benzoxazinone, by 2 the insertion fatty amines of nucleophilic reaction at quinazolinone ring, maintain the temperature at 170 degree, and namely formamide several minutes obtains target product.
(3) react with sulphur cyanogen or thiocyanates: Smits etc. reflux in DMSO with 2-amino-5-chloro-benzoic acid, cyclization is reacted again with rhodan ammonium, generate 2-sulfo-quinazolinones, again by steps such as replacements, synthesize the chloro-2-of target product 6-(4-methylpiperazine-1-yl) quinazoline-4 (3H)-one.
2) take anthranilamide as raw material
(1) react with aldehydes: Mehdi Bakavoli etc. with anthranilamide and various aldehyde compound in water, with I
2/ KI is that catalyzer and oxygenant carry out dioxide giving reaction, obtains target product.This reaction conditions is gentle, environment-friendly and green, and the reaction times is short, and condition is easy to realize.
(2) react with diethyl oxalate: the anthranilamide such as Baker and oxalic acid diethyl ester react cyclization, yield 57%.The method raw material is easy to get, and device is simple, but the productive rate of the quianzolinones of synthesis is not high.
3) take cinnamyl o-aminobenzoate as raw material
(1) first with after ethylene glycol monoethyl ether sodium demineralizing acid react cyclization with 2-amino-5-methylbenzoic acid ethyl ester again with guanidine or Guanidinium hydrochloride such as Guanidinium hydrochloride annulation: Acharya etc., yield can reach 79% ~ 82%.This method is simple to operate, and yield is high, a kind of good method of synthesizing quianzolinones of can yet be regarded as.
(2) cyclization is reacted with different sulphur cyanogen: Alagarsamy etc. form quinazoline female ring compound with 2-Methyl anthranilate and the different sulphur cyanogen of 1--2-methylbenzene closed loop, and yield is 60%.The method is complicated, long reaction time and productive rate is not high.
4) take o-Cyanoaniline as raw material
(1) react with amino or dicyanodiamide or guanidine: cover little Ying etc. with 2-aminotoluene through nitrated, replace, reduce and obtain 2-methyl-6-anthranilo nitrile, react cyclization with amino or dicyanodiamide or guanidine again to obtain, this step productive rate is 80%, then through nitrated, reduce to obtain target compound.
(2) with CO
2reaction: Mizuno etc. are with a series of 2-amino 4,5-disubstituted benzenes formonitrile HCN and CO
2reaction cyclization, yield is 93% ~ 97%.Such operation is simple, and a step just can synthetic product, and productive rate is high and by product is few, but R and R ' be meta-orienting group as nitro time, this reaction can not be carried out.
5) with o-amino benzoyl ketone for raw material
(1) react with aldehyde, ammonium acetate: zhan-hui zhang etc. are with maltose-DMU-NH
4this low melting point salt of Cl is solvent, under the condition of catalyst-free, o-amino benzoyl ketone and aldehyde, ammonium acetate are reacted and can obtain target product under 90 degree, yield is more than 80%, but the raw material of this building-up reactions is more complicated, more difficult preparation, and X group wherein must be electron withdrawing group, and this reaction could occur.
(2) react with benzylamine: K.Karnakar etc. take graphite oxide as catalyzer, and acetonitrile is solvent, and under 70-75 degree, adjacent amino aryl ketone musk and benzylamine are reacted 24 hours, namely obtain target product, yield is more than 70%.But this reaction is only limitted to and benzylamine reaction, namely can only generate the quinazoline that 2-phenyl replaces, and can not generate the quinazoline that 2 are alkyl.
Utilize aforesaid method to prepare quinazoline derivant in the lab, have obvious shortcoming: in these synthetic methods of quinazoline, some method raw materials are cheap and easy to get, but synthetic route is long, and productive rate is not high; Some method stepss are comparatively easy, but reaction substrate is complicated, and agents useful for same toxicity is large; Some method speed of reaction are fast, need the time short, but reaction configuration requirement is high; The reaction yield also had is high, but has certain limitation, and is difficult to synthesize polysubstituted quinazoline derivant, especially polysubstituted the or polysubstituted quinazoline derivant of pyrimidine ring of highly selective synthesis phenyl ring.
Summary of the invention
For solving the problem, the present invention proposes a kind of preparation method of polysubstituted quinazoline derivant.
A preparation method for polysubstituted quinazoline derivant, described polysubstituted quinazoline derivant has the structure shown in formula I:
Wherein, R
1, R
2, R
3, R
4, R
5, R
6all be selected from the one in hydrogen atom, halogen atom, saturated alkyl, unsaturated alkyl, substituted alkyl, aryl, substituted aryl, ester group, acyl group, nitro, alkoxyl group;
Described aryl is phenyl, thienyl, furyl, pyrryl, pyridyl or naphthyl;
The substituting group of described substituted alkyl, substituted aryl is the one in halogen atom, saturated alkyl, unsaturated alkyl, substituted alkyl, aryl, substituted aryl, ester group, acyl group, nitro, alkoxyl group;
Comprise the following steps:
To in reactor, add diaryl high price salt compounded of iodine, mantoquita, after substituting nitrogen three times, adds solvent, adds nitrile in two steps subsequently; If the nitrile added is identical, then once add, add twice amount of substance; Reaction is heated to complete after reinforced; After reaction system cooling, add water or salts solution cancellation reaction, add methylene dichloride, K
2cO
3, stir process, and divide with methylene dichloride and extract for three times, merge organic phase, add dried over mgso, filter, rotary evaporation concentrated filtrate obtains crude product, and crude product eluent column chromatography for separation, obtains product; Its chemical process is shown in reaction formula (1).
reaction formula (1)
Described diaryl high price salt compounded of iodine molecular formula is Ar
2i
+x
-; Wherein Ar is aryl and substituted aryl; Described aryl is phenyl, thienyl, furyl, pyrryl, pyridyl or naphthyl; The substituting group of described substituted aryl is the one in halogen atom, saturated alkyl, unsaturated alkyl, substituted alkyl, aryl, substituted aryl, ester group, acyl group, nitro, alkoxyl group;
X
-for negatively charged ion, be selected from fluorine, chlorine, bromine, iodide ion, Tetrafluoroboric acid group, trifluoromethanesulfonic acid group, the one in phosphofluoric acid group, tosate, benzene sulfonic acid group, methylsulfonic acid group.
Its molecular formula of described nitrile is R
1cN or R
2cN; Wherein R
1and R
2be respectively the one in hydrogen atom, halogen atom, saturated alkyl, unsaturated alkyl, substituted alkyl, aryl, substituted aryl, ester group, acyl group, nitro, alkoxyl group.
Described mantoquita is selected from the one in cuprous chloride, cuprous bromide, cuprous iodide, cuprous sulfide, cuprous cyanide, cupric chloride, cupric bromide, cupric fluoride, copper trifluoromethanesulfcomposite, Tetrafluoroboric acid copper, cupric perchlorate, cupric nitrate, copper sulfate, methyl ethyl diketone, neutralized verdigris.
Described solvent is selected from the one in tetrahydrofuran (THF), dioxane, benzene, toluene, phenylfluoroform, acetonitrile, methylene dichloride, trichloromethane, ethylene dichloride, ethyl acetate, ether, methyl tert butyl ether, normal hexane, hexanaphthene, sherwood oil.
Described solvent needs before use through anhydrous and oxygen-free process.
The molar ratio that diaryl high price salt compounded of iodine and two steps add the nitrile in nitrile is 1:(1-2): (1-2).
The mol ratio of described mantoquita and diaryl high price salt compounded of iodine is 5% ~ 100%.
Reaction times is: 2h ~ 2d.
The temperature of described heating is: 50 DEG C ~ 150 DEG C.
Beneficial effect of the present invention is: the preparation method of polysubstituted quinazoline derivant provided by the present invention is scientific and reasonable, can synthesize obtain other method be difficult to the polysubstituted quinazoline derivant that synthesizes, and synthetic method is simple, productive rate is high, product is easy to the features such as purifying.
Accompanying drawing explanation
Fig. 1 is the compound of embodiment 2 preparation
1h NMR collection of illustrative plates.
Fig. 2 is the compound of embodiment 5 preparation
1h NMR collection of illustrative plates.
Fig. 3 is the compound of embodiment 8 preparation
1h NMR collection of illustrative plates.
Fig. 4 is the compound of embodiment 11 preparation
1h NMR collection of illustrative plates.
Embodiment
Below by specific embodiment, method of the present invention is described, but the present invention is not limited thereto.
Experimental technique described in following embodiment, if no special instructions, is ordinary method; Described reagent and material, if no special instructions, all can obtain from commercial channels.
Solvent used in following embodiment all carries out simple process through anhydrous and oxygen-free process or the molecular sieve after adding activation before using.
The preparation of embodiment 1,2,4-bis--p-methylphenyl quinazoline (R in structural formula I
1=R
2=p-methylphenyl, R
3=R
4=R
5=R
6=hydrogen)
To in the reactor of 25mL, add phenylbenzene high price salt compounded of iodine (1mmol, R
3=R
4=R
5=R
6=hydrogen), copper trifluoromethanesulfcomposite (10% of phenylbenzene high price salt compounded of iodine amount of substance), after substituting nitrogen three times, adds solvent (3mL), adds methyl cyanophenyl (3mmol) subsequently, react 12 hours after reinforced under 130 ° of C.After reaction system cooling, add 5mL shrend and to go out reaction, add 5mL methylene dichloride, K
2cO
3solid (2mmol), stir process 1h, and divide with 30mL methylene dichloride and extract for three times, filtrate merges, and adds dried over mgso 30 minutes, filters, and filtrate rotary evaporation is concentrated obtains crude product.Crude product eluent post is separated (200-300 order silica gel), obtains white solid product 2, the 4-bis-p-methylphenyl quinazoline 273mg that purity is greater than 99%, isolated yield 88%.
The Structural Identification of 2,4-bis-p-methylphenyl quinazoline
Nuclear magnetic resonance data:
1H NMR(301MHz,CHLOROFORM-D)δ8.73(d,J=8.1Hz,2H),8.16(dd,J=11.0,8.5Hz,2H),7.82(dd,J=13.8,7.9Hz,3H),7.51-7.37(m,5H),2.52(s,3H),2.50(s,3H).
13C NMR(76MHz,CHLOROFORM-D)δ168.22,160.40,152.19,140.76,140.17,135.83,135.14,133.45,130.40(CH×2),129.45(CH×2),129.39(CH×2),129.20,128.87(CH×2),127.16,126.76,121.75,21.76,21.65.
GC-MS data: m/z=310
Analytical results shows, the target product of acquisition is correct.
The preparation of embodiment 2,2,4-di-p-methoxy phenylquinazoline (R in structural formula I
1=R
2=p-methoxyphenyl, R
3=R
4=R
5=R
6=hydrogen)
To in the reactor of 25mL, add phenylbenzene high price salt compounded of iodine (1mmol, R
3=R
4=R
5=R
6=hydrogen), copper trifluoromethanesulfcomposite (10% of phenylbenzene high price salt compounded of iodine amount of substance), to methoxy cyanophenyl (3mmol), after substituting nitrogen three times, adds solvent (3mL), reacts 12 hours after reinforced under 130 ° of C.After reaction system cooling, add 5mL shrend and to go out reaction, add 5mL methylene dichloride, K
2cO
3solid (2mmol), stir process 1h, and divide with 30mL methylene dichloride and extract for three times, filtrate merges, and adds dried over mgso 30 minutes, filters, and filtrate rotary evaporation is concentrated obtains crude product.Crude product eluent post is separated (200-300 order silica gel), obtains white solid product 2, the 4-di-p-methoxy phenylquinazoline 308mg that purity is greater than 99%, isolated yield 90%.
The Structural Identification of 2,4-di-p-methoxy phenylquinazoline:
Nuclear magnetic resonance data, as shown in Figure 1:
1H NMR(400MHz,CHLOROFORM-D)δ8.70-8.64(m,2H),8.13(d,J=8.3Hz,1H),8.09(d,J=8.6Hz,1H),7.88(d,J=8.5Hz,2H),7.83(m,1H),7.49(m,1H),7.14-7.08(m,2H),7.07-7.01(m,2H),3.91(s,3H),3.89(s,3H).
13C NMR(101MHz,CHLOROFORM-D)δ167.62,161.78,161.25,160.01,152.21,133.40,131.94,131.10,130.35(CH×2,C×1),128.99,127.15,126.48,121.43,114.07(CH×2),113.91(CH×2),55.57,55.47.
GC-MS data: m/z=342.
Analytical results shows, the target product of acquisition is correct.
The preparation of embodiment 3,2,4-bis-p-trifluoromethyl phenyl quinazoline (R in structural formula I
1=R
2=p-trifluoromethyl phenyl, R
3=R
4=R
5=R
6=hydrogen)
To in the reactor of 25mL, add phenylbenzene high price salt compounded of iodine (1mmol, R
3=R
4=R
5=R
6=hydrogen), copper trifluoromethanesulfcomposite (10% of phenylbenzene high price salt compounded of iodine amount of substance), pchlorobenzotrifluoride (3mmol), after substituting nitrogen three times, adds solvent (3mL), reacts 12 hours after reinforced under 130 ° of C.After reaction system cooling, add 5mL shrend and to go out reaction, add 5mL methylene dichloride, K
2cO
3solid (2mmol), stir process 1h, and divide with 30mL methylene dichloride and extract for three times, filtrate merges, and adds dried over mgso 30 minutes, filters, and filtrate rotary evaporation is concentrated obtains crude product.Crude product eluent post is separated (200-300 order silica gel), obtains white solid product 2, the 4-bis-p-trifluoromethyl phenyl quinazoline 276mg that purity is greater than 99%, isolated yield 66%.
The Structural Identification of 2,4-bis-p-trifluoromethyl phenyl quinazoline:
Nuclear magnetic resonance data:
1H NMR(400MHz,CHLOROFORM-D)δ8.76(d,J=7.0Hz,2H),8.15(d,J=8.2Hz,1H),8.03(d,J=7.6Hz,1H),7.97(d,J=6.7Hz,2H),7.95-7.90(m,1H),7.88(d,J=7.6Hz,2H),7.75(d,J=6.8Hz,2H),7.64-7.56(m,1H).
13C NMR(101MHz,CHLOROFORM-D)δ167.05,158.73,151.93,141.17,140.86,134.18,132.22(q,J=32.2Hz),132.06(q,J=32.7Hz),130.58(CH×2),129.55,128.90(CH×2),128.09,126.44,125.66(d,J=3.4Hz,CH×2),125.50(d,J=3.5Hz,CH×2),124.31(q,J=272.5Hz),124.07(q,J=272.5Hz),121.69.
GC-MS data: m/z=418
Analytical results shows, the target product of acquisition is correct.
The preparation of embodiment 4,2,4-bis--(2-thiophene) quinazoline (R in structural formula I
1=R
2=2-thiophene, R
3=R
4=R
5=R
6=hydrogen)
To in the reactor of 25mL, add phenylbenzene high price salt compounded of iodine (1mmol, R
3=R
4=R
5=R
6=hydrogen), copper trifluoromethanesulfcomposite (10% of phenylbenzene high price salt compounded of iodine amount of substance), 2-cyano thiophene (3mmol), after substituting nitrogen three times, adds solvent (3mL), reacts 12 hours after reinforced under 130 ° of C.After reaction system cooling, add 5mL shrend and to go out reaction, add 5mL methylene dichloride, K
2cO
3solid (2mmol), stir process 1h, and divide with 30mL methylene dichloride and extract for three times, filtrate merges, and adds dried over mgso 30 minutes, filters, and filtrate rotary evaporation is concentrated obtains crude product.Crude product eluent post is separated (200-300 order silica gel), obtains yellow solid product 2,4-bis--(2-thiophene) the quinazoline 235mg that purity is greater than 99%, isolated yield 80%.
The Structural Identification of 2,4-bis--(2-thiophene) quinazoline:
Nuclear magnetic resonance data:
1H NMR(400MHz,CHLOROFORM-D)δ8.41(dd,J=11.0,3.1Hz,1H),8.20(dd,J=3.7,1.2Hz,1H),8.02(d,J=8.5Hz,1H),7.89-7.85(m,1H),7.85-7.78(m,1H),7.64(dd,J=5.0,0.8Hz,1H),7.55-7.49(m,2H),7.24(dd,J=5.0,3.7Hz,1H),7.20(dd,J=5.0,3.7Hz,1H).
13C NMR(101MHz,CHLOROFORM-D)δ160.43,156.99,152.33,144.03,141.51,133.82,131.36,130.77,129.97,129.37,129.02,128.37,128.27,127.19,126.19,120.43.
GC-MS data: m/z=294
Analytical results shows, the target product of acquisition is correct.
The preparation of embodiment 5,2,4-phenylbenzene-5,8-dimethyl quinazoline (R in structural formula I
1=R
2=phenyl, R
3=R
6=methyl, R
4=R
5=hydrogen)
To in the reactor of 25mL, add two-2,5-3,5-dimethylphenyl high price salt compounded of iodine (1mmol, R
3=R
6=methyl, R
4=R
5=hydrogen), copper trifluoromethanesulfcomposite (10% of phenylbenzene high price salt compounded of iodine amount of substance), cyanophenyl (3mmol), after substituting nitrogen three times, adds solvent (3mL), reacts 12 hours after reinforced under 130 ° of C.After reaction system cooling, add 5mL shrend and to go out reaction, add 5mL methylene dichloride, K
2cO
3solid (2mmol), stir process 1h, and divide with 30mL methylene dichloride and extract for three times, filtrate merges, and adds dried over mgso 30 minutes, filters, and filtrate rotary evaporation is concentrated obtains crude product.Crude product eluent post is separated (200-300 order silica gel), obtains white solid product 2,4-phenylbenzene-5, the 8-dimethyl quinazoline 260mg that purity is greater than 99%, isolated yield 84%.
The Structural Identification of 2,4-phenylbenzene-5,8-dimethyl quinazoline:
Nuclear magnetic resonance data, as shown in Figure 2:
1H NMR(400MHz,CHLOROFORM-D)δ8.75(dd,J=8.0,1.4Hz,2H),7.61(d,J=7.2Hz,1H),7.59-7.56(m,2H),7.55-7.47(m,6H),7.21(d,J=7.2Hz,1H),2.91(s,3H),2.05(s,3H).
13C NMR(101MHz,CHLOROFORM-D)δ168.63,157.49,152.02,142.50,138.36,135.31,133.48,133.12,130.37,129.67,129.16(CH×2),129.06,128.72(CH×2),128.55(CH×2),128.30(CH×2),122.09,23.91,17.88.
ESI data: m/z=310
Analytical results shows, the target product of acquisition is correct.
The preparation of embodiment 6,2,4-phenylbenzene-6-trifluoromethyl quinazoline (R in structural formula I
1=R
2=phenyl, R
4=trifluoromethyl, R
3=R
5=R
6=hydrogen)
To in the reactor of 25mL, add two p-trifluoromethyl phenyl high price salt compounded of iodine (1mmol, R
4=trifluoromethyl, R
3=R
5=R
6=hydrogen), copper trifluoromethanesulfcomposite (10% of phenylbenzene high price salt compounded of iodine amount of substance), cyanophenyl (3mmol), after substituting nitrogen three times, adds solvent (3mL), reacts 12 hours after reinforced under 130 ° of C.After reaction system cooling, add 5mL shrend and to go out reaction, add 5mL methylene dichloride, K
2cO
3solid (2mmol), stir process 1h, and divide with 30mL methylene dichloride and extract for three times, filtrate merges, and adds dried over mgso 30 minutes, filters, and filtrate rotary evaporation is concentrated obtains crude product.Crude product eluent post is separated (200-300 order silica gel), obtains white solid product 2, the 4-phenylbenzene-6-trifluoromethyl quinazoline 245mg that purity is greater than 99%, isolated yield 70%.
The Structural Identification of 2,4-phenylbenzene-6-trifluoromethyl quinazoline:
Nuclear magnetic resonance data:
1H NMR(400MHz,CHLOROFORM-D)δ8.71(dd,J=5.5,2.3Hz,2H),8.42(s,1H),8.23(d,J=8.8Hz,1H),8.03(d,J=8.8Hz,1H),7.91-7.86(m,2H),7.67-7.60(m,3H),7.57-7.51(m,3H).
13C NMR(101MHz,CHLOROFORM-D)δ169.36,161.92,153.38,137.57,136.92,131.30,130.62,130.60,130.30(CH×2),129.23(q,J=2.6Hz),129.05(CH×2),128.97(CH×2),128.73(CH×2),128.67(q,J=32.9Hz),125.19(q,J=3.8Hz),123.94(q,J=272.4Hz),120.78.
GC-MS data: m/z=350
Analytical results shows, the target product of acquisition is correct.
The preparation of embodiment 7,2,4-phenylbenzene-6-fluquinconazole quinoline (R in structural formula I
1=R
2=phenyl, R
4=fluorine, R
3=R
5=R
6=hydrogen)
To in the reactor of 25mL, add two couples of fluorophenyl high price salt compounded of iodine (1mmol, R
4=fluorine, R
3=R
5=R
6=hydrogen), copper trifluoromethanesulfcomposite (10% of phenylbenzene high price salt compounded of iodine amount of substance), cyanophenyl (3mmol), after substituting nitrogen three times, adds solvent (3mL), reacts 12 hours after reinforced under 130 ° of C.After reaction system cooling, add 5mL shrend and to go out reaction, add 5mL methylene dichloride, K
2cO
3solid (2mmol), stir process 1h, and divide with 30mL methylene dichloride and extract for three times, filtrate merges, and adds dried over mgso 30 minutes, filters, and filtrate rotary evaporation is concentrated obtains crude product.Crude product eluent post is separated (200-300 order silica gel), obtains white solid product 2, the 4-phenylbenzene-6-fluquinconazole quinoline 270mg that purity is greater than 99%, isolated yield 90%.
The Structural Identification of 2,4-phenylbenzene-6-fluquinconazole quinoline:
Nuclear magnetic resonance data:
1H NMR(400MHz,CHLOROFORM-D)δ8.69(m,2H),8.16(dd,J=9.2,5.3Hz,1H),7.91-7.86(m,2H),7.75(dd,J=9.2,2.8Hz,1H),7.68-7.64(m,1H),7.64-7.60(m,3H),7.57-7.51(m,3H).
13C NMR(101MHz,CHLOROFORM-D)δ167.87(d,J=5.5Hz),161.70,159.98,159.22,149.25,137.68(d,J=63.3Hz),131.89(d,J=8.5Hz),130.70,130.26,130.06(CH×2),128.83(CH×2),128.68(CH×2),128.65(CH×2),123.97(d,J=25.8Hz),122.16(d,J=9.2Hz),110.48(d,J=23.1Hz).
GC-MS data: m/z=300
Analytical results shows, the target product of acquisition is correct
The preparation of embodiment 8,2-p-methoxyphenyl-4-butyl quinazoline (R in structural formula I
1=p-methoxyphenyl, R
2=butyl, R
3=R
4=R
5=R
6=hydrogen)
To in the reactor of 25mL, add phenylbenzene high price salt compounded of iodine (1.0mmol, R
3=R
4=R
5=R
6=hydrogen), copper trifluoromethanesulfcomposite (20% of phenylbenzene high price salt compounded of iodine amount of substance), to methoxy cyanophenyl (1mmol), after substituting nitrogen three times, add solvent (3mL), under 120 ° of C, reacting 30min after reinforced, to be cooledly to room temperature, add valeronitrile (2mmol), continuing reacting by heating 12h to reacting complete.After reaction system cooling, add 5mL shrend and to go out reaction, add 5mL methylene dichloride, K
2cO
3solid (2mmol), stir process 1h, and divide with 30mL methylene dichloride and extract for three times, filtrate merges, and adds dried over mgso 30 minutes, filters, and filtrate rotary evaporation is concentrated obtains crude product.Crude product eluent post is separated (200-300 order silica gel), obtains the white solid product 2-p-methoxyphenyl-4-butyl quinazoline 187mg that purity is greater than 99%, isolated yield 64%.
The Structural Identification of 2-p-methoxyphenyl-4-butyl quinazoline:
Nuclear magnetic resonance data, as shown in Figure 3.
1H NMR(400MHz,CHLOROFORM-D)δ8.61(d,J=8.9Hz,2H),8.08(d,J=8.2Hz,1H),8.03(d,J=8.4Hz,1H),7.83-7.78(m,1H),7.54-7.48(m,1H),7.04(d,J=8.9Hz,2H),3.89(s,3H),3.30(t,J=7.6Hz,2H),2.00-1.91(m,2H),1.60-1.47(m,2H),1.03(t,J=7.4Hz,3H).
13C NMR(76MHz,CHLOROFORM-D)δ171.39,161.72,159.97,150.88,133.26,131.32,130.28(CH×2),129.26,126.33,124.71,122.34,113.94(CH×2),55.47,34.39,30.74,22.92,14.13.
GC-MS data: m/z=292
Analytical results shows, the target product of acquisition is correct.
The preparation of embodiment 9,2-(2-thiophene)-4-butyl quinazoline (R in structural formula I
1=2-thiophene, R
2=butyl, R
3=R
4=R
5=R
6=hydrogen)
To in the reactor of 25mL, add phenylbenzene high price salt compounded of iodine (1.0mmol, R
3=R
4=R
5=R
6=hydrogen), copper trifluoromethanesulfcomposite (20% of phenylbenzene high price salt compounded of iodine amount of substance), 2-cyano thiophene (1mmol), after substituting nitrogen three times, add solvent (3mL), under 120 ° of C, reacting 45min after reinforced, to be cooledly to room temperature, add valeronitrile (2mmol), continuing reacting by heating 12h to reacting complete.After reaction system cooling, add 5mL shrend and to go out reaction, add 5mL methylene dichloride, K
2cO
3solid (2mmol), stir process 1h, and divide with 30mL methylene dichloride and extract for three times, filtrate merges, and adds dried over mgso 30 minutes, filters, and filtrate rotary evaporation is concentrated obtains crude product.Crude product eluent post is separated (200-300 order silica gel), obtains white solid product 2-(2-the thiophene)-4-butyl quinazoline 169mg that purity is greater than 99%, isolated yield 63%.
The Structural Identification of 2-(2-thiophene)-4-butyl quinazoline:
Nuclear magnetic resonance data:
1H NMR(301MHz,CHLOROFORM-D)δ8.15(dd,J=3.7,1.2Hz,1H),8.06(dd,J=8.2,0.6Hz,1H),7.99(d,J=8.5Hz,1H),7.81(ddd,J=8.3,6.9,1.3Hz,1H),7.55-7.47(m,2H),7.18(dd,J=5.0,3.7Hz,1H),3.28(t,J=7.8Hz,2H),1.99-1.88(m,2H),1.59-1.46(m,2H),1.02(t,J=7.3Hz,3H).
13C NMR(76MHz,CHLOROFORM-D)δ171.76,157.16,150.65,144.59,133.53,129.67,129.05(CH×2),128.28,126.53,124.80,122.48,34.19,30.61,22.86,14.09.
GC-MS data: m/z=268
Analytical results shows, the target product of acquisition is correct.
The preparation of embodiment 10,2-p-methoxyphenyl-4-bromine quinazoline (R in structural formula I
1=p-methoxyphenyl, R
2=bromine, R
3=R
4=R
5=R
6=hydrogen)
To in the reactor of 25mL, add phenylbenzene high price salt compounded of iodine (1.0mmol, R
3=R
4=R
5=R
6=hydrogen), copper trifluoromethanesulfcomposite (20% of phenylbenzene high price salt compounded of iodine amount of substance), to methoxy cyanophenyl (1mmol), after substituting nitrogen three times, add solvent (3mL), under 120 ° of C, reacting 30min after reinforced, to be cooledly to room temperature, add cyanogen bromide (2mmol), continuing reacting by heating 12h to reacting complete.After reaction system cooling, add 5mL shrend and to go out reaction, add 5mL methylene dichloride, K
2cO
3solid (2mmol), stir process 1h, and divide with 30mL methylene dichloride and extract for three times, filtrate merges, and adds dried over mgso 30 minutes, filters, and filtrate rotary evaporation is concentrated obtains crude product.Crude product eluent post is separated (200-300 order silica gel), obtains the white solid product 2-p-methoxyphenyl-4-bromine quinazoline 188mg that purity is greater than 99%, isolated yield 60%.
The Structural Identification of 2-p-methoxyphenyl-4-bromine quinazoline:
Nuclear magnetic resonance data:
1H NMR(301MHz,CHLOROFORM-D)δ8.47-8.42(m,2H),8.04(dd,J=8.3,0.8Hz,1H),7.90(d,J=8.7Hz,1H),7.81-7.74(m,1H),7.53-7.47(m,1H),6.92(dd,J=9.4,2.4Hz,2H),3.80(s,3H).
13C NMR(101MHz,CHLOROFORM-D)δ162.33,159.97,157.06,151.45,134.75,130.59(CH×2),128.78,128.23,127.94,125.90,124.49,114.07(CH×2),55.50.
GC-MS data: m/z=314
Analytical results shows, the target product of acquisition is correct.
The preparation of embodiment 11,2-p-methoxyphenyl-4-chloromethyl quinazoline (R in structural formula I
1=p-methoxyphenyl, R
2=chloromethyl, R
3=R
4=R
5=R
6=hydrogen)
To in the reactor of 25mL, add phenylbenzene high price salt compounded of iodine (1.0mmol, R
3=R
4=R
5=R
6=hydrogen), copper trifluoromethanesulfcomposite (20% of phenylbenzene high price salt compounded of iodine amount of substance), to methoxy cyanophenyl (1mmol), after substituting nitrogen three times, add solvent (3mL), under 120 ° of C, reacting 30min after reinforced, to be cooledly to room temperature, add chloromethyl cyanide (2mmol), continuing reacting by heating 12h to reacting complete.After reaction system cooling, add 5mL shrend and to go out reaction, add 5mL methylene dichloride, K
2cO
3solid (2mmol), stir process 1h, and divide with 30mL methylene dichloride and extract for three times, filtrate merges, and adds dried over mgso 30 minutes, filters, and filtrate rotary evaporation is concentrated obtains crude product.Crude product eluent post is separated (200-300 order silica gel), obtains the yellow solid product 2-p-methoxyphenyl-4-chloromethyl quinazoline 148mg that purity is greater than 99%, isolated yield 52%.
The Structural Identification of 2-p-methoxyphenyl-4-chloromethyl quinazoline:
Nuclear magnetic resonance data, as shown in Figure 4.
1H NMR(301MHz,CHLOROFORM-D)δ8.50-8.45(m,2H),8.03(d,J=8.3Hz,1H),7.95(d,J=8.4Hz,1H),7.77-7.70(m,1H),7.48-7.41(m,1H),6.95-6.89(m,2H),4.97(s,2H),3.78(s,3H).
13C NMR(101MHz,CHLOROFORM-D)δ164.37,162.01,160.11,151.78,134.02,130.41,130.37(CH×2),129.42,127.06,124.59,121.04,114.02(CH×2),55.48,43.95.
GC-MS data: m/z=284
Analytical results shows, the target product of acquisition is correct.
The preparation of embodiment 12,2-p-methoxyphenyl-4-carbamoyl ethyl base quinazoline (R in structural formula I
1=p-methoxyphenyl, R
2=carbamoyl ethyl, R
3=R
4=R
5=R
6=hydrogen)
To in the reactor of 25mL, add phenylbenzene high price salt compounded of iodine (1.0mmol, R
3=R
4=R
5=R
6=hydrogen), copper trifluoromethanesulfcomposite (20% of phenylbenzene high price salt compounded of iodine amount of substance), to methoxy cyanophenyl (1mmol), after substituting nitrogen three times, add solvent (3mL), under 120 ° of C, reacting 30min after reinforced, to be cooledly to room temperature, add ethyl cyanoformate (2mmol), continuing reacting by heating 12h to reacting complete.After reaction system cooling, add 5mL shrend and to go out reaction, add 5mL methylene dichloride, K
2cO
3solid (2mmol), stir process 1h, and divide with 30mL methylene dichloride and extract for three times, filtrate merges, and adds dried over mgso 30 minutes, filters, and filtrate rotary evaporation is concentrated obtains crude product.Crude product eluent post is separated (200-300 order silica gel), obtains the white solid product 2-p-methoxyphenyl-4-carbamoyl ethyl base quinazoline 169mg that purity is greater than 99%, isolated yield 55%.
The Structural Identification of 2-p-methoxyphenyl-4-carbamoyl ethyl base quinazoline:
Nuclear magnetic resonance data:
1H NMR(301MHz,CHLOROFORM-D)δ8.52(d,J=8.8Hz,2H),8.33(d,J=8.4Hz,1H),8.01(d,J=8.5Hz,1H),7.81(t,J=7.6Hz,1H),7.52(t,J=7.6Hz,1H),6.96(d,J=8.8Hz,2H),4.54(q,J=7.1Hz,2H),3.82(s,3H),1.45(t,J=7.1Hz,3H).
13C NMR(76MHz,CHLOROFORM-D)δ165.43,162.16,160.13,157.71,152.55,134.38,130.50(CH×2),130.18,129.08,127.76,125.91,120.14,114.07(CH×2),62.61,55.49,14.41.
GC-MS data: m/z=308
Analytical results shows, the target product of acquisition is correct.
The preparation of embodiment 13,2-(1-naphthyl)-4-butyl quinazoline (R in structural formula I
1=1-naphthyl, R
2=butyl, R
3=R
4=R
5=R
6=hydrogen)
To in the reactor of 25mL, add phenylbenzene high price salt compounded of iodine (1.0mmol, R
3=R
4=R
5=R
6=hydrogen), copper trifluoromethanesulfcomposite (20% of phenylbenzene high price salt compounded of iodine amount of substance), 1-naphthalene nitrile (1mmol), after substituting nitrogen three times, add solvent (3mL), under 120 ° of C, reacting 120min after reinforced, to be cooledly to room temperature, add valeronitrile (2mmol), continuing reacting by heating 12h to reacting complete.After reaction system cooling, add 5mL shrend and to go out reaction, add 5mL methylene dichloride, K
2cO
3solid (2mmol), stir process 1h, and divide with 30mL methylene dichloride and extract for three times, filtrate merges, and adds dried over mgso 30 minutes, filters, and filtrate rotary evaporation is concentrated obtains crude product.Crude product eluent post is separated (200-300 order silica gel), obtains white solid product 2-(1-the naphthyl)-4-butyl quinazoline 187mg that purity is greater than 99%, isolated yield 60%.
The Structural Identification of 2-(1-naphthyl)-4-butyl quinoline azoles:
Nuclear magnetic resonance data:
1H NMR(301MHz,CHLOROFORM-D)δ8.75-8.64(m,1H),8.19(dd,J=10.7,6.7Hz,3H),8.01-7.87(m,3H),7.64(t,J=7.7Hz,2H),7.58-7.48(m,2H),3.40(t,J=7.8Hz,2H),2.05-1.87(m,2H),1.64-1.48(m,2H),1.04(t,J=7.3Hz,3H).
13C NMR(76MHz,CHLOROFORM-D)δ171.93,162.86,150.68,136.91,134.35,133.66,131.46,130.20,129.55,129.51,128.53,127.34,126.73,126.27,125.90,125.46,124.82,122.16,34.72,31.40,23.08,14.12.
GC-MS data: m/z=312
Analytical results shows, the target product of acquisition is correct.
Claims (10)
1. a preparation method for polysubstituted quinazoline derivant, described polysubstituted quinazoline derivant has the structure shown in formula I:
Wherein, R
1, R
2, R
3, R
4, R
5, R
6all be selected from the one in hydrogen atom, halogen atom, saturated alkyl, unsaturated alkyl, substituted alkyl, aryl, substituted aryl, ester group, acyl group, nitro, alkoxyl group;
Described aryl is phenyl, thienyl, furyl, pyrryl, pyridyl or naphthyl;
The substituting group of described substituted alkyl, substituted aryl is the one in halogen atom, saturated alkyl, unsaturated alkyl, substituted alkyl, aryl, substituted aryl, ester group, acyl group, nitro, alkoxyl group;
It is characterized in that, comprise the following steps:
To in reactor, add diaryl high price salt compounded of iodine, mantoquita, after substituting nitrogen three times, adds solvent, adds nitrile in two steps subsequently; If the nitrile added is identical, then once add, add twice amount of substance; Reaction is heated to complete after reinforced; After reaction system cooling, add water or salts solution cancellation reaction, add methylene dichloride, K
2cO
3, stir process, and divide with methylene dichloride and extract for three times, merge organic phase, add dried over mgso, filter, rotary evaporation concentrated filtrate obtains crude product, and crude product eluent column chromatography for separation, obtains product; Its chemical process is shown in reaction formula (1):
2. preparation method according to claim 1, is characterized in that, described diaryl high price salt compounded of iodine molecular formula is Ar
2i
+x
-; Wherein Ar is aryl and substituted aryl; Described aryl is phenyl, thienyl, furyl, pyrryl, pyridyl or naphthyl; The substituting group of described substituted aryl is the one in halogen atom, saturated alkyl, unsaturated alkyl, substituted alkyl, aryl, substituted aryl, ester group, acyl group, nitro, alkoxyl group;
X
-for negatively charged ion, be selected from fluorine, chlorine, bromine, iodide ion, Tetrafluoroboric acid group, trifluoromethanesulfonic acid group, the one in phosphofluoric acid group, tosate, benzene sulfonic acid group, methylsulfonic acid group.
3. preparation method according to claim 1, is characterized in that, its molecular formula of described nitrile is R
1cN or R
2cN; Wherein R
1and R
2be respectively the one in hydrogen atom, halogen atom, saturated alkyl, unsaturated alkyl, substituted alkyl, aryl, substituted aryl, ester group, acyl group, nitro, alkoxyl group.
4. preparation method according to claim 1, it is characterized in that, described mantoquita is selected from the one in cuprous chloride, cuprous bromide, cuprous iodide, cuprous sulfide, cuprous cyanide, cupric chloride, cupric bromide, cupric fluoride, copper trifluoromethanesulfcomposite, Tetrafluoroboric acid copper, cupric perchlorate, cupric nitrate, copper sulfate, methyl ethyl diketone, neutralized verdigris.
5. preparation method according to claim 1, it is characterized in that, described solvent is selected from the one in tetrahydrofuran (THF), dioxane, benzene, toluene, phenylfluoroform, acetonitrile, methylene dichloride, trichloromethane, ethylene dichloride, ethyl acetate, ether, methyl tert butyl ether, normal hexane, hexanaphthene, sherwood oil.
6. preparation method according to claim 1, is characterized in that, described solvent needs before use through anhydrous and oxygen-free process.
7. preparation method according to claim 1, is characterized in that, the molar ratio that diaryl high price salt compounded of iodine and two steps add the nitrile in nitrile is 1:(1-2): (1-2).
8. preparation method according to claim 1, is characterized in that, the mol ratio of described mantoquita and diaryl high price salt compounded of iodine is 5% ~ 100%.
9. preparation method according to claim 1, is characterized in that, the reaction times is: 2h ~ 2d.
10. preparation method according to claim 1, is characterized in that, the temperature of described heating is: 50 DEG C ~ 150 DEG C.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1188476A (en) * | 1995-06-21 | 1998-07-22 | 萨诺费公司 | 4-phenylaminothiazole derivatives, method for preparing same, and pharmaceutical compositions thereof |
| CN1665791A (en) * | 2002-07-05 | 2005-09-07 | 霍夫曼-拉罗奇有限公司 | Quinazoline derivatives |
| CN1678613A (en) * | 2002-08-30 | 2005-10-05 | 诺瓦提斯公司 | Hetereoaryl nitrile derivatives |
| US20070015024A1 (en) * | 2005-07-15 | 2007-01-18 | Honda Motor Co., Ltd. | Membrane-electrode assembly for solid polymer electrolyte fuel cell |
| CN101056865A (en) * | 2004-11-09 | 2007-10-17 | 霍夫曼-拉罗奇有限公司 | Aminoquinazolines compounds |
| CN103140466A (en) * | 2010-08-04 | 2013-06-05 | 第一三共株式会社 | Process for preparing compound by novel sandmeyer-like reaction using nitroxide radical compound as reaction catalyst |
-
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1188476A (en) * | 1995-06-21 | 1998-07-22 | 萨诺费公司 | 4-phenylaminothiazole derivatives, method for preparing same, and pharmaceutical compositions thereof |
| CN1665791A (en) * | 2002-07-05 | 2005-09-07 | 霍夫曼-拉罗奇有限公司 | Quinazoline derivatives |
| CN1678613A (en) * | 2002-08-30 | 2005-10-05 | 诺瓦提斯公司 | Hetereoaryl nitrile derivatives |
| CN101056865A (en) * | 2004-11-09 | 2007-10-17 | 霍夫曼-拉罗奇有限公司 | Aminoquinazolines compounds |
| US20070015024A1 (en) * | 2005-07-15 | 2007-01-18 | Honda Motor Co., Ltd. | Membrane-electrode assembly for solid polymer electrolyte fuel cell |
| CN103140466A (en) * | 2010-08-04 | 2013-06-05 | 第一三共株式会社 | Process for preparing compound by novel sandmeyer-like reaction using nitroxide radical compound as reaction catalyst |
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