CN103275016B - Synthetic method of 2-subsituted quinazoline compounds - Google Patents
Synthetic method of 2-subsituted quinazoline compounds Download PDFInfo
- Publication number
- CN103275016B CN103275016B CN201310219956.6A CN201310219956A CN103275016B CN 103275016 B CN103275016 B CN 103275016B CN 201310219956 A CN201310219956 A CN 201310219956A CN 103275016 B CN103275016 B CN 103275016B
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- synthetic method
- mol ratio
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Abstract
The invention relates to a synthetic method of 2-subsituted quinazoline compounds. In the synthetic method, copper compounds and cerium compounds are adopted to serve as bi-component catalysts, and the 2-subsituted quinazoline compounds are prepared by reacting 2-aminobenzyl alcohols with aromatic aldehyde compounds in organic solvents in the presence of ammonium sources. The synthetic method is easy to operate, high in product yield and purity, is a novel synthetic method for preparation of the 2-subsituted quinazoline compounds, and has a good industrial prospect and potential application value.
Description
Technical field
The present invention relates to a kind of synthetic method of nitrogen heterocyclic ring compounds, particularly a kind of synthetic method of 2-substituted quinazoline compounds, belongs to organic chemical synthesis field.
Background technology
In miscellaneous nitrogen-containing heterocycle compound, quinazoline compounds has good biological activity because of it, and it is had a wide range of applications and Research Prospects in the fields such as medicine and agricultural chemicals.
Quinazoline compounds has very strong restraining effect to EGF-R ELISA (EGFR) and Tyrosylprotein kinase (EGFR-TK), can be used for anticancer.In addition, quinazoline compounds also has sterilization, desinsection, antiviral, many medical applications such as anti-inflammatory, hypertension, tuberculosis, part quinazoline compounds becomes commercial pharmaceutical, as cancer therapy drug Gefitinib, germ killing drugs third oxygen quinoline etc. simultaneously.Just because of application prospect widely and the potential therapeutic action of quinazoline compounds, the synthesis of its respective compound and bioactivity research had become a pharmaceutical chemical study hotspot and emphasis already.
At present, the preparation method of 2-aryl-quinazoline compounds can be divided into two classes according to the difference of reaction conditions: the first kind is the catalysis annulation of metal superlattice, mainly adopt transition metal palladium, copper etc. as catalyzer, organic amine and corresponding aromatic aldehyde or amide compound cyclization are formed.Equations of The Second Kind is then use strong oxidizer as DDQ, MnO
2, the deoxidation such as NaClO changes into ring.
Charles E.Villars reports with 2-pimelinketone ethyl acetate for raw material prepares 2-Ban Ji-5,6,7,8-tetrahydro-quinazoline, and then at 300 DEG C, catalyzing by metal palladium dehydrogenation generates 2-phenylquinazoline, and its reaction formula is as follows:
2006, the people such as Sorensen reported under Pd catalysis, and 2-chloro-quinazoline and phenylo boric acid carry out linked reaction, and generate 2-phenylquinazoline, and reaction formula is as follows:
2009, people's benzamidine hydrochlorid such as Michelle Morrow and adjacent benzaldehyde iodine carried out linked reaction and obtain 2-phenylquinazoline under metal catalytic, and reaction formula is as follows:
2010, the people such as Fu were with Liv Ullmann linked reaction model, and use more economical acid amides to synthesize 2-substituted quinazoline compounds for reaction substrate, reaction formula is as follows:
The people such as Pike report a kind of method that there is lower synthesis 2-substituted quinazoline compounds without metal, and described method is with MnO
2for oxygenant, reaction formula is as follows:
The people such as Wang use I2/TBHP as oxidation system, and synthesized disubstituted quinazoline compound with 2-aminobenzophenone and benzylamine for raw material, its reaction formula is as follows:
The people such as Reddy report with aromatic aldehyde and o-amino-benzylamine for raw material, and under oxidizing dehydrogenation, form 2-substituted quinazoline compounds, its reaction formula is as follows:
Although there is the synthetic method of above-mentioned multiple 2-substituted quinazoline compounds in prior art, but all there is certain defect in these methods, such as raw material is difficult to obtain (as o-amino-benzylamine not easily synthesizes, expensive), need that precious metal, reaction scheme are too loaded down with trivial details, productive rate and purity is all lower, severe reaction conditions need finely control etc.
Therefore, for easy, be easy to process, the synthetic method of the 2-substituted quinazoline compounds of reaction conditions gentleness, still there is the necessity proceeding to study and explore, this be also medicine intermediate field for large the determined active demand of 2-substituted quinazoline compounds demand, be also one of current study hotspot.
Summary of the invention
In order to overcome above-mentioned pointed many defects, seeking to synthesize the brand-new of 2-substituted quinazoline compounds and simple method, present inventor has performed deep research, after having paid a large amount of creative works, thus complete the present invention.
Specifically, technical scheme of the present invention and content relate to the synthetic method of the 2-substituted quinazoline compounds shown in following formula (I), described method comprises: under bicomponent catalyst, ammonium source compound, alkali and the oxygen existence that copper compound and cerium compound form, undertaken reacting and obtained described formula (I) compound in reaction solvent by the adjacent aminobenzyl alcohol compound of formula (II) and formula (III) Aromatic aldehyde compound;
Wherein R is selected from C independently of one another
1-C
6alkyl, halogen, halo C
1-C
6alkyl, halo C
1-C
6alkoxyl group or nitro;
N is the integer of 0-4;
Ar is selected from arbitrary group in (A)-(D) as follows:
Wherein R
1be selected from C independently of one another
1-C
6alkyl, C
1-C
6alkoxyl group, halogen, halo C
1-C
6alkyl or halo C
1-C
6alkoxyl group;
M is the integer of 0-5;
X, Y are selected from N, O or S independently of one another;
represent and be connected with the 2-position of quinazoline compound formula (I) Suo Shi or be connected with the aldehyde radical in formula (III).
In described synthetic method of the present invention, unless otherwise prescribed, from start to finish, C
1-C
6the implication of alkyl refers to the straight or branched alkyl with 1-6 carbon atom, that includes C
1alkyl, C
2alkyl, C
3alkyl, C
4alkyl, C
5alkyl or C
6alkyl, such as can be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl or n-hexyl etc. in non-limiting manner.
In described synthetic method of the present invention, unless otherwise prescribed, from start to finish, C
1-C
6alkoxyl group refers to " C defined above
1-C
6alkyl " be connected with O atom after group.
In described synthetic method of the present invention, unless otherwise prescribed, from start to finish, the implication of halogen refers to haloid element, non-exclusively such as can be F, Cl, Br or I.
In described synthetic method of the present invention, unless otherwise prescribed, from start to finish, halo C
1-C
6the implication of alkyl refers to the " C defined above be optionally substituted by halogen
1-C
6alkyl ", be such as trifluoromethyl, pentafluoroethyl group, difluoromethyl, chloromethyl etc. in non-limiting manner.
In described synthetic method of the present invention, unless otherwise prescribed, from start to finish, halo C
1-C
6the implication of alkoxyl group refers to the " C defined above be optionally substituted by halogen
1-C
6alkoxyl group ", be such as trifluoromethoxy, five fluorine oxyethyl groups, difluoro-methoxy, chlorine methoxyl group etc. in non-limiting manner.
In described synthetic method of the present invention, n is the integer of 0-4, such as, can be 0,1,2,3 or 4, when for 0 time, mean to there is not substituent R.When n is greater than 1, then can carries out group selection independently between n R, namely be selected from C independently of one another
1-C
6alkyl, halogen, halo C
1-C
6alkyl, halo C
1-C
6alkoxyl group or nitro.
In described synthetic method of the present invention, m is the integer of 0-5, such as, can be 0,1,2,3,4 or 5, when for 0 time, mean to there is not substituent R
1.When m is greater than 1, then m R
1between can carry out group selection independently, be namely selected from C independently of one another
1-C
6alkyl, C
1-C
6alkoxyl group, halogen, halo C
1-C
6alkyl or halo C
1-C
6alkoxyl group.
In described synthetic method of the present invention, the described copper compound as catalyst component is monovalence copper compound, cupric compound or both mixtures.
Described monovalence copper compound is selected from inorganic monovalent copper compound or monovalence organocopper compound, such as can be CuCl, CuBr, CuI, Cu (OTf), Cu in non-limiting manner
2sO
4, Cu
2in S etc. any one or multiple.
Described cupric compound is selected from divalent inorganic copper compound or divalence organocopper compound, such as can be CuCl in non-limiting manner
2, CuBr
2, CuI
2, CuSO
4, venus crystals [Cu (OAc)
2], acetylacetone copper [Cu (acac)
2], Cu (OTf)
2deng in any one or multiple.
Described copper compound is preferably monovalence copper compound, is more preferably inorganic monovalent copper compound, most preferably is CuCl.
In described synthetic method of the present invention, in non-limiting manner, the described cerium compound as catalyst component is selected from Ce (NO
3)
3, CeCl
3, Ce
2(SO
4)
3in any one or multiple, in their hydrate any one or multiple, such as Ce (NO
3)
36H
2o, CeCl
37H
2o, Ce
2(SO
4)
38H
2in O etc. any one or multiple, most preferably be Ce (NO
3)
3or Ce (NO
3)
36HxO.
In described synthetic method of the present invention, described alkali is alkali-metal oxyhydroxide or alkali-metal carbonate, such as can be NaOH, LiOH, KOH, Na in non-limiting manner
2cO
3, K
2cO
3, Li
2cO
3in any one or multiple, most preferably be KOH.
In described synthetic method of the present invention, described ammonium source compound is various Inorganic Ammonium or organic ammonium, such as can be in non-limiting manner in ammonium chloride, ammonium sulfate, ammonium acetate, ammoniacal liquor etc. any one or multiple, wherein ammoniacal liquor mass concentration can be 15-30%, most preferably is ammonium chloride.
In described synthetic method of the present invention, reaction solvent when formula (II) and (III) react is one or more in acetonitrile, tetrahydrofuran (THF) (THF), DMF (DMF), ethanol, methylene dichloride, dimethyl sulfoxide (DMSO) (DMSO), 2-methyltetrahydrofuran, methylene dichloride, trichloromethane, tetracol phenixin, ethylene dichloride, normal hexane, ether, methyl alcohol, ethanol, n-propyl alcohol, Virahol, butanols, amylalcohol, hexanol, acetone etc.Most preferably be acetonitrile.
In described synthetic method of the present invention, formula (II) is 1:1-3 with the mol ratio of formula (III) compound, such as can be 1:1,1:1.5,1:2,1:2.5 or 1:3 in non-limiting manner.
In described synthetic method of the present invention, the mol ratio of formula (II) compound and copper compound is 1:0.05-0.3, such as can be 1:0.05,1:0.1,1:0.15,1:0.2,1:0.25 or 1:0.3 in non-limiting manner.
In described synthetic method of the present invention, the mol ratio of formula (II) compound and cerium compound is 1:0.05-0.3, such as can be 1:0.05,1:0.1,1:0.15,1:0.2,1:0.25 or 1:0.3 in non-limiting manner.
In described synthetic method of the present invention, the mol ratio of formula (II) compound and ammonium source compound is 1:1-3, such as can be 1:1,1:1.5,1:2,1:2.5 or 1:3 in non-limiting manner.
In described synthetic method of the present invention, the mol ratio of formula (II) compound and alkali is 1:1-3, such as can be 1:1,1:1.5,1:2,1:2.5 or 1:3 in non-limiting manner.
In described synthetic method of the present invention, temperature of reaction is 60-120 DEG C, such as can be 60 DEG C, 70 DEG C, 80 DEG C, 90 DEG C, 100 DEG C, 110 DEG C or 120 DEG C in non-limiting manner.
In described synthetic method of the present invention, reaction times, there is no particular limitation, such as detect the residual quantity of raw material by liquid chromatography or TLC how many and determine the suitable reaction times, it typically is 12-30 hour, is such as 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 26 hours, 28 hours or 30 hours in non-limiting manner.
In described synthetic method of the present invention, described reaction is reacted in the presence of oxygen, such as, oxygen can be continued to be passed in reaction system, or in oxygen atmosphere, carry out described reaction of the present invention.
In described synthetic method of the present invention, as a kind of combined method of proportioning between various raw material, can be as follows:
Formula (II) is 1:1-3 with the mol ratio of formula (III) compound, and/or
The mol ratio of formula (II) compound and copper compound is 1:0.05-0.3, and/or
The mol ratio of formula (II) compound and cerium compound is 1:0.05-0.3, and/or
The mol ratio of formula (II) compound and ammonium source compound is 1:1-3, and/or
The mol ratio of formula (II) compound and alkali is 1:1-3.
In described synthetic method of the present invention, select the citing of preferred implementation as some key element a kind of, can be as follows:
Described copper compound is CuCl, and/or
Described cerium compound is Ce (NO
3)
3or Ce (NO
3)
36H
2o, and/or
Described alkali is KOH, and/or
Described ammonium source compound is ammonium chloride, and/or
Described reaction solvent is acetonitrile.
In described synthetic method of the present invention, aftertreatment after reaction terminates can adopt any known conventional processing means, such as, any one process means in crystallization, recrystallization, chromatography over CC, extraction etc. or the combination of multiple process means in organic synthesis field.As a kind of exemplary aftertreatment means, such as can be: with Rotary Evaporators from the mixture that obtains after reaction terminates except desolventizing, residue is crossed 200-500 order silica gel column chromatography and is carried out purifying and obtaining target product, and column chromatography procedure can TLC tracing and monitoring and determine suitable wash-out terminal.
Exemplify as one is exemplary, the R in structural formula (I) and formula (II) can be H, F, Cl, methyl or nitro.
Exemplify as one is exemplary, the R in structural formula (A) and (C)
1can be phenyl, p-methylphenyl, to fluorophenyl, to fluoroform phenyl or 4-pyridyl.
Exemplify as one is exemplary, Ar can be phenyl, to fluorophenyl, rubigan, p-methylphenyl, to fluoroform phenyl, p-methoxyphenyl, 2,6-dichlorophenyl, 2-furyl, 2-thienyl, 2-naphthyl, benzo [1,3] dioxolane-5-base etc.
In sum, the present invention uses adjacent aminobenzyl alcohol and aromatic aldehyde compound to be raw material first, and select suitable copper compound and cerium compound as catalyzer, under ammonium source compound and alkali exist, and formula (II) and (III) compound one step can be made to obtain 2-substituted quinazoline compounds compounds, described method reaction is simple, easy and simple to handle, yield and purity high, it is a kind of brand-new synthetic method of 2-substituted quinazoline compounds, preparation for this compounds provides new synthetic route, there is good researching value and prospects for commercial application.
Embodiment
Below by specific embodiment, the present invention is described in detail; but the purposes of these exemplary embodiments and object are only used for exemplifying the present invention; not any type of any restriction is formed to real protection scope of the present invention, more non-protection scope of the present invention is confined to this.
The synthesis of embodiment 1:2-phenylquinazoline
In four mouthfuls of reactors of dried and clean, add 50ml solvent acetonitrile, then add above formula (II) compound, formula (III) compound, CuCl, Ce (NO successively
3)
3, ammonium chloride, KOH, make its mol ratio be 1:1:0.05:0.05:1:1, its Chinese style (II) compound is 10mmol.Reaction system reacted 30 hours at 60 DEG C, period continues bubbling and passes into oxygen.
After reaction terminates, with Rotary Evaporators from the mixture that obtains after reaction terminates except desolventizing, residue is crossed 200 silica gel column chromatographies and is carried out purifying and obtaining target product, and productive rate is 97.5%, and purity is 98.9% (HPLC).
Fusing point: 97-98 DEG C.
Nucleus magnetic resonance:
1h NMR (DMSO-d
6, 500MHz) and δ 9.71 (s, 1H), 8.56-8.59 (m, 2H); 8.17 (d, J=8.0Hz, 1H), 8.01-8.08 (m, 2H); 7.72-7.77 (m, 1H), 7.56-7.59 (m, 3H);
13C NMR(DMSO-d
6,125MHz):δ161.2,159.7,149.9,137.5,134.8,130.4,128.6(2C),128.0,127.8(2C),127.7,127.5,123.2。
The synthesis of embodiment 2:2-(4-fluorophenyl) quinazoline
In four mouthfuls of reactors of dried and clean, add 45ml solvent acetonitrile, then add above formula (II) compound, formula (III) compound, CuCl, Ce (NO successively
3)
36H
2o, ammonium sulfate, KOH, make its mol ratio be 1:1.5:0.1:0.1:1.5:1.5, its Chinese style (II) compound is 10mmol.Reaction system reacted 26 hours at 70 DEG C, period continues bubbling and passes into oxygen.
After reaction terminates, with Rotary Evaporators from the mixture that obtains after reaction terminates except desolventizing, residue is crossed 300 silica gel column chromatographies and is carried out purifying and obtaining target product, and productive rate is 99.2%, and purity is 99.5% (HPLC).
Fusing point: 135-137 DEG C.
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) and δ 9.43 (s, 1H), 8.60-8.64 (m, 2H), 8.06 (d; J=8.3Hz, 1H), 7.89 (t, J=8.1Hz, 2H), 7.60 (t; J=7.2Hz, 1H), 7.20 (t, J=8.4Hz, 2H);
13C NMR(CDCl
3,125MHz):δ164.7(d,
1J
C-F=245.1Hz,1C),160.6,160.2,150.7,134.1,130.8,130.6,128.4(2C),127.3,127.1,123.4,115.5(d,
2J
C-F=21.2Hz,2C)。
The synthesis of embodiment 3:2-(2-tolyl) quinazoline
In four mouthfuls of reactors of dried and clean, add 50ml solvent acetonitrile, then add above formula (II) compound, formula (III) compound, CuCl, CeCl successively
3, ammonium chloride, KOH, make its mol ratio be 1:2:0.15:0.15:2:2, its Chinese style (II) compound is 10mmol.Reaction system reacted 22 hours at 80 DEG C, period continues bubbling and passes into oxygen.
After reaction terminates, with Rotary Evaporators from the mixture that obtains after reaction terminates except desolventizing, residue is crossed 400 silica gel column chromatographies and is carried out purifying and obtaining the target product into sticky oil thing, and productive rate is 97.6%, and purity is 98.6% (HPLC).
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) and δ 9.50 (s, 1H), 8.10 (d; J=8.3Hz, 1H), 7.89-7.94 (m, 2H); 7.77 (d, J=7.6Hz, 1H), 7.63 (t; J=7.6Hz, 1H), 7.45 (t; J=7.5Hz, 1H), 7.06-7.11 (m; 2H), 3.86 (s, 3H);
13C NMR(CDCl
3,125MHz):δ162.5,159.9,157.6,150.5,134.0,131.7,130.7,128.9,128.4,127.4,127.0,123.0,120.6,111.9,55.9。
The synthesis of embodiment 4:2-(2,4 dichloro benzene base) quinazoline
In four mouthfuls of reactors of dried and clean, add 55ml solvent acetonitrile, then add above formula (II) compound, formula (III) compound, CuCl, Ce (NO successively
3)
3, ammonium chloride, KOH, make its mol ratio be 1:2.5:0.2:0.2:2.5:2.5, its Chinese style (II) compound is 10mmol.Reaction system reacted 18 hours at 90 DEG C, period continues bubbling and passes into oxygen.
After reaction terminates, with Rotary Evaporators from the mixture that obtains after reaction terminates except desolventizing, residue is crossed 500 silica gel column chromatographies and is carried out purifying and obtaining target product, and productive rate is 98.2%, and purity is 98.8% (HPLC).
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) and δ 9.55 (s, 1H), 8.16 (d, J=8.5Hz, 1H), 7.96-8.03 (m, 2H), 7.71-7.75 (m, 1H), 7.31-7.46 (m, 3H);
13C NMR(CDCl
3,125MHz):δ160.7,160.3,150.4,137.7,134.5,134.1(2C),130.3,128.5,128.4,128.1(2C),127.3,123.5。
The synthesis of embodiment 5:2-(1-naphthyl) quinazoline
In four mouthfuls of reactors of dried and clean, add 48ml solvent acetonitrile, then add above formula (II) compound, formula (III) compound, CuCl, Ce (NO successively
3)
36H
2o, ammonium acetate, KOH, make its mol ratio be 1:3:0.25:0.25:3:3, its Chinese style (II) compound is 10mmol.Reaction system reacted 14 hours at 100 DEG C, period continues bubbling and passes into oxygen.
After reaction terminates, with Rotary Evaporators from the mixture that obtains after reaction terminates except desolventizing, residue is crossed 250 silica gel column chromatographies and is carried out purifying and obtaining target product, and productive rate is 93.9%, and purity is 99.1% (HPLC).
Fusing point: 120-121 DEG C.
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) and δ 9.61 (s, 1H); 8.70 (d, J=8.1Hz, 1H); 8.16-8.19 (m, 2H), 7.94-8.03 (m; 4H), 7.70 (t, J=7.6Hz; 1H), 7.64 (t, J=7.6Hz; 1H), 7.51-7.57 (m, 2H);
13C NMR(CDCl
3,125MHz):δ163.4,160.2,150.7,136.1,134.2,134.0,131.1,130.4,129.5,128.6,128.4,127.6,127.0,126.7,125.8,125.6,125.1,123.0。
The synthesis of embodiment 6:2-(2-thienyl) quinazoline
In four mouthfuls of reactors of dried and clean, add 45ml solvent acetonitrile, then add above formula (II) compound, formula (III) compound, CuCl, Ce (NO successively
3)
36H
2o, ammonium acetate, KOH, make its mol ratio be 1:1:0.3:0.3:2.5:2.5, its Chinese style (II) compound is 10mmol.Reaction system reacted 12 hours at 110 DEG C, period continues bubbling and passes into oxygen.
After reaction terminates, with Rotary Evaporators from the mixture that obtains after reaction terminates except desolventizing, residue is crossed 350 silica gel column chromatographies and is carried out purifying and obtaining target product, and productive rate is 99.7%, and purity is 99.3% (HPLC).
Fusing point: 132-134 DEG C.
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) and δ 9.33 (s, 1H), 8.13-8.16 (m, 1H); 8.00 (d, J=8.6Hz, 1H), 7.84-7.88 (m, 2H); 7.53-7.58 (m, 2H), 7.17-7.21 (m, 1H);
13C NMR(CDCl
3,125MHz):δ159.4,156.8,149.5,142.7,133.4,128.8,128.1,127.4,127.2,126.1,125.9,122.4。
The synthesis of embodiment 7:2-(2-furyl) quinazoline
In four mouthfuls of reactors of dried and clean, add 55ml solvent acetonitrile, then add above formula (II) compound, formula (III) compound, CuCl, Ce (NO successively
3)
36H
2o, ammonium chloride, KOH, make its mol ratio be 1:2:0.05:0.05:2:2, its Chinese style (II) compound is 10mmol.Reaction system reacted 24 hours at 120 DEG C, period continues bubbling and passes into oxygen.
After reaction terminates, with Rotary Evaporators from the mixture that obtains after reaction terminates except desolventizing, residue is crossed 450 silica gel column chromatographies and is carried out purifying and obtaining target product, and productive rate is 98.6%, and purity is 99.2% (HPLC).
Fusing point: 131-132 DEG C.
Nucleus magnetic resonance: 1H NMR (CDCl
3, 500MHz) and δ 9.37 (s, 1H); 8.07 (d, J=8.5Hz, 1H); 7.86-7.90 (m, 2H), 7.67 (s; 1H), 7.61 (t, J=6.0Hz; 1H), 7.44-7.46 (m, 1H); 6.60-6.63 (m, 1Hz);
13C NMR(CDCl
3,125MHz):δ160.6,154.0,152.4,150.3,145.2,134.4,128.3,127.1,127.0,123.3,114.0,112.2。
The synthesis of embodiment 8:2-benzo [1,3] dioxolane-5-base-quinazoline
In four mouthfuls of reactors of dried and clean, add 50ml solvent acetonitrile, then add above formula (II) compound, formula (III) compound, CuCl, Ce (NO successively
3)
36H
2o, mass concentration are ammoniacal liquor, the KOH of 20%, make its mol ratio be that (wherein ammoniacal liquor is with NH for 1:3:0.3:0.1:1:3
3meter), its Chinese style (II) compound is 10mmol.Reaction system reacted 28 hours at 70 DEG C, period continues bubbling and passes into oxygen.
After reaction terminates, with Rotary Evaporators from the mixture that obtains after reaction terminates except desolventizing, residue is crossed 500 silica gel column chromatographies and is carried out purifying and obtaining target product, and productive rate is 91.6%, and purity is 97.9% (HPLC).
Nucleus magnetic resonance:
1h NMR (DMSO-d
6, 500MHz) and δ 9.62 (s, 1H), 8.13-8.19 (m, 2H), 7.98-8.00 (m, 3H), 7.67-7.71 (m, 1H), 7.08 (d, J=8.0Hz, 1H), 6.13 (s, 2H);
13C NMR(DMSO-d
6,125MHz):δ161.0,159.4,149.9,149.6,147.8,134.6,131.8,127.7,127.6,127.3,123.1,123.0,108.3,107.5,101.4。
The synthesis of embodiment 9:2-(3-fluoroform phenyl) quinazoline
In four mouthfuls of reactors of dried and clean, add 50ml solvent acetonitrile, then add above formula (II) compound, formula (III) compound, CuCl, Ce (NO successively
3)
3, ammonium chloride, KOH, make its mol ratio be 1:2:0.1:0.3:3:1.5, its Chinese style (II) compound is 10mmol.Reaction system reacted 23 hours at 90 DEG C, period continues bubbling and passes into oxygen.
After reaction terminates, with Rotary Evaporators from the mixture that obtains after reaction terminates except desolventizing, residue is crossed 200 silica gel column chromatographies and is carried out purifying and obtaining target product, and productive rate is 98.2%, and purity is 99.3% (HPLC).
Nucleus magnetic resonance:
1h NMR (DMSO-d
6, 500MHz) and δ 9.75 (s, 1H), 8.75 (d, J=8.5Hz, 2H), 8.21 (d, J=8.0Hz, 1H), 8.06-8.12 (m, 2H), 7.93 (d, J=8.5Hz, 2H), 7.78-7.82 (m, 1H);
13C NMR(DMSO-d
6,125MHz):δ161.5,158.3,149.7,141.2,135.1,130.7,130.4,128.7,127.8,126.3(2C),125.6(q,J=273Hz,1C),125.1(2C),123.2。
The synthesis of the fluoro-2-phenylquinazoline of embodiment 10:6-
In four mouthfuls of reactors of dried and clean, add 50ml solvent acetonitrile, then successively
Add above formula (II) compound, formula (III) compound, CuCl, Ce (NO
3)
3, ammonium chloride, KOH, make its mol ratio be 1:1:0.25:0.1:1:2.5, its Chinese style (II) compound is 10mmol.Reaction system reacted 20 hours at 100 DEG C, period continues bubbling and passes into oxygen.
After reaction terminates, with Rotary Evaporators from the mixture that obtains after reaction terminates except desolventizing, residue is crossed 300 silica gel column chromatographies and is carried out purifying and obtaining target product, and productive rate is 97.9%, and purity is 98.8% (HPLC).
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) and δ 9.44 (s, 1H), 8.58-8.61 (m, 2H), 8.08-8.12 (m, 1H), 7.64-7.70 (m, 1H), 7.50-7.55 (m, 4H);
13C NMR(CDCl
3,125MHz):δ161.2(d,
1J
C-F=243.2Hz,1C),159.6,159.2,148.1,137.7,131.2,130.6,128.7(2C),128.5(2C),124.5,123.8,110.1(d,
2J
C-F=21.0Hz,1C)。
The synthesis of embodiment 11:8-methyl-2-phenylquinazoline
In four mouthfuls of reactors of dried and clean, add 55ml solvent acetonitrile, then add above formula (II) compound, formula (III) compound, CuCl, Ce (NO successively
3)
3, ammonium sulfate, KOH, make its mol ratio be 1:1.5:0.05:0.3:1.5:1, its Chinese style (II) compound is 10mmol.Reaction system reacted 17 hours at 110 DEG C, period continues bubbling and passes into oxygen.
After reaction terminates, with Rotary Evaporators from the mixture that obtains after reaction terminates except desolventizing, residue is crossed 400 silica gel column chromatographies and is carried out purifying and obtaining target product, and productive rate is 97.2%, and purity is 98.6% (HPLC).
Nucleus magnetic resonance:
1h NMR (DMSO-d
6, 500MHz) and δ 9.63 (s, 1H), 8.57-8.60 (m, 2H); 7.96 (d, J=8.0Hz, 1H), 7.86 (d, J=7.0Hz; 1H), 7.74-7.62 (m, 4H), 2.78 (s, 3H);
13C NMR(DMSO-d
6,125MHz):δ160.4,159.7,149.3,138.1,137.3,136.3,130.2,128.6(2C),128.3,128.1(2C),125.7,123.5,21.6。
The synthesis of embodiment 12:7-nitro-2-phenylquinazoline
In four mouthfuls of reactors of dried and clean, add 60ml solvent acetonitrile, then add above formula (II) compound, formula (III) compound, CuCl, CeCl successively
3, ammoniacal liquor, KOH, make its mol ratio be that (wherein ammoniacal liquor is with NH to 1:3:0.1:0.2:3:2.5
3meter), its Chinese style (II) chemical combination
Thing is 10mmol.Reaction system reacted 13 hours at 120 DEG C, period continues bubbling and passes into oxygen.
After reaction terminates, with Rotary Evaporators from the mixture that obtains after reaction terminates except desolventizing, residue is crossed 500 silica gel column chromatographies and is carried out purifying and obtaining target product, and productive rate is 96.1%, and purity is 98.7% (HPLC).
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) and δ 9.61 (s, 1H), 8.96 (d, J=2.0Hz; 1H), 8.63-8.66 (m, 2H), 8.34-8.38 (m, 1H); 8.10 (d, J=8.5Hz, 1H), 7.54-7.58 (m, 3H);
13C NMR(CDCl
3,125MHz):δ162.8,160.6,151.1,150.4,136.7,131.5,128.9,128.7(2C),128.6(2C),125.6,124.8,120.5。
Can being found out by above-described embodiment 1-12, when adopting described method of the present invention, 2-substituted quinazoline compounds can be obtained with high yield, high purity.
Embodiment 13-24
Replace with except following copper compound except by CuCl wherein, implement embodiment 13-24 respectively in the mode identical with embodiment 1-12, use the yield of copper compound, embodiment corresponding relation and corresponding product as shown in the table.
| Project | Copper compound | Corresponding embodiment | Yield (%) |
| Embodiment 13 | CuI | Embodiment 1 | 61 |
| Embodiment 14 | CuBr | Embodiment 2 | 58 |
| Embodiment 15 | Cu(OTf) | Embodiment 3 | 60 |
| Embodiment 16 | Cu 2SO 4 | Embodiment 4 | 59 |
| Embodiment 17 | Cu 2S | Embodiment 5 | 65 |
| Embodiment 18 | Cu(acac) 2 | Embodiment 6 | 32 |
| Embodiment 19 | CuI 2 | Embodiment 7 | 44 |
| Embodiment 20 | CuSO 4 | Embodiment 8 | 41 |
| Embodiment 21 | CuBr 2 | Embodiment 9 | 38 |
| Embodiment 22 | Cu(OAc) 2 | Embodiment 10 | 46 |
| Embodiment 23 | Cu | Embodiment 11 | 18 |
| Embodiment 24 | Cu(OTf) 2 | Embodiment 12 | 43 |
As seen from the above table, when other copper compound of use especially monovalence copper compound, corresponding product can be obtained equally, but productive rate is wanted significantly lower than productive rate during CuCl, even if when employing and CuCl negatively charged ion belong to Br, I of gang together, when namely adopting CuBr or CuI, its productive rate is also remarkable in productive rate during CuCl.
It can also be seen that, the catalytic effect of monovalence copper compound will significantly be better than cupric effect, and such as during use CuBr, productive rate is 58%, and CuBr
2be only 38%.
Embodiment 25-48
Except wherein all not adding except copper compound, respectively to implement embodiment 37-48 with the same way of embodiment 1-12.
Except wherein all not adding except cerium compound, respectively to implement embodiment 37-48 with the same way of embodiment 1-12.
Result is as following table.
| Project | Products collection efficiency (%) |
| Embodiment 25-36 | <5 |
| Embodiment 37-48 | Trace |
As seen from the above table, when not using copper compound, the equal <5% of products collection efficiency, without any actual application value.And ought not use outside cerium compound, then react and almost can not carry out.This demonstrate that the bicomponent catalyst of the method for the invention, cerium compound especially wherein has specific single-minded catalytic to this reaction.
Embodiment 49-60
Replace with except following alkali except by KOH wherein, implement embodiment 49-60 respectively in the mode identical with embodiment 1-12, use the yield of alkali, embodiment corresponding relation and corresponding product as shown in the table.
| Project | Alkali | Corresponding embodiment | Products collection efficiency (%) |
| Embodiment 49 | Li 2CO 3 | Embodiment 1 | 32 |
| Embodiment 50 | K 2CO 3 | Embodiment 2 | 45 |
| Embodiment 51 | CsOAc | Embodiment 3 | 17 |
| Embodiment 52 | KF | Embodiment 4 | 17 |
| Embodiment 53 | t-BuOK | Embodiment 5 | 33 |
| Embodiment 54 | Urotropine | Embodiment 6 | <5 |
| Embodiment 55 | LiOH | Embodiment 7 | 46 |
| Embodiment 56 | K 3PO 4 | Embodiment 8 | 14 |
| Embodiment 57 | Trolamine | Embodiment 9 | 9 |
| Embodiment 58 | NaOH | Embodiment 10 | 45 |
| Embodiment 59 | DABCO * | Embodiment 11 | NR |
| Embodiment 60 | Na 2CO 3 | Embodiment 12 | 29 |
*: DABCO is Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane
NR: unreacted.
As seen from the above table, when using other alkali outside KOH as alkali-metal carbonate and LiOH, NaOH, although productive rate decreases, but still described method can be carried out smoothly.Other alkali as organic bases then productive rate significantly reduce, even can not react, this demonstrate that alkali-metal oxyhydroxide or carbonate have promoter action to described reaction, especially KOH has the most excellent promoter action.
In sum, can clearly be found out by above-mentioned all embodiments, when applying the method according to the invention, object product 2-substituted quinazoline compounds can be obtained with high yield and high purity smoothly by adjacent aminobenzyl alcohol and aromatic aldehyde compound, a kind of brand-new synthetic method having very much prospects for commercial application, for the efficient quick synthesis of 2-substituted quinazoline compounds provides brand-new synthetic route.
Should be appreciated that the purposes of these embodiments is only not intended to for illustration of the present invention limit the scope of the invention.In addition; also should understand; after having read technology contents of the present invention, those skilled in the art can make various change, amendment and/or modification to the present invention, and these all equivalent form of values fall within the protection domain that the application's appended claims limits equally.
Claims (5)
1. the synthetic method of 2-substituted quinazoline compounds shown in a formula (I), described method comprises: under bicomponent catalyst, ammonium source compound, alkali and the oxygen existence that copper compound and cerium compound form, undertaken reacting and obtained described formula (I) compound in reaction solvent by the adjacent aminobenzyl alcohol compound of formula (II) and formula (III) Aromatic aldehyde compound;
Wherein R is selected from C independently of one another
1-C
6alkyl, halogen, halo C
1-C
6alkyl, halo C
1-C
6alkoxyl group or nitro;
N is the integer of 0-4;
Ar is selected from arbitrary group in (A)-(D) as follows:
Wherein R
1independently selected from C
1-C
6alkyl, C
1-C
6alkoxyl group, halogen, halo C
1-C
6alkyl or halo C
1-C
6alkoxyl group;
M is the integer of 0-5;
X, Y are selected from N, O or S independently of one another;
Wherein, described copper compound is CuCl, CuBr, CuI, Cu (OTf), Cu
2sO
4, Cu
2any one in S;
Described cerium compound is selected from Ce (NO
3)
3, CeCl
3in any one, or any one in their hydrate;
Described ammonium source compound be in ammonium chloride, ammonium sulfate, ammonium acetate, ammoniacal liquor any one or multiple;
Described alkali is KOH.
2. synthetic method as claimed in claim 1, it is characterized in that: described reaction solvent is one or more in acetonitrile, tetrahydrofuran (THF), DMF, ethanol, methylene dichloride, dimethyl sulfoxide (DMSO), 2-methyltetrahydrofuran, methylene dichloride, trichloromethane, tetracol phenixin, ethylene dichloride, normal hexane, ether, methyl alcohol, ethanol, n-propyl alcohol, Virahol, butanols, amylalcohol, hexanol, acetone.
3. synthetic method as claimed in claim 1, is characterized in that: temperature of reaction is 60-120 DEG C; Reaction times is 12-30 hour.
4. synthetic method as claimed in claim 1, is characterized in that:
Formula (II) is 1:1-3 with the mol ratio of formula (III) compound, and/or
The mol ratio of formula (II) compound and copper compound is 1:0.05-0.3, and/or
The mol ratio of formula (II) compound and cerium compound is 1:0.05-0.3, and/or
The mol ratio of formula (II) compound and ammonium source compound is 1:1-3, and/or
The mol ratio of formula (II) compound and alkali is 1:1-3.
5. the synthetic method as described in any one of claim 1-4, is characterized in that:
Described copper compound is CuCl, and/or
Described cerium compound is Ce (NO
3)
3or Ce (NO
3)
36H
2o, and/or
Described ammonium source compound is ammonium chloride, and/or
Described reaction solvent is acetonitrile.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310219956.6A CN103275016B (en) | 2013-06-04 | 2013-06-04 | Synthetic method of 2-subsituted quinazoline compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310219956.6A CN103275016B (en) | 2013-06-04 | 2013-06-04 | Synthetic method of 2-subsituted quinazoline compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103275016A CN103275016A (en) | 2013-09-04 |
| CN103275016B true CN103275016B (en) | 2015-03-11 |
Family
ID=49057664
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310219956.6A Expired - Fee Related CN103275016B (en) | 2013-06-04 | 2013-06-04 | Synthetic method of 2-subsituted quinazoline compounds |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103275016B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105272926B (en) * | 2014-07-24 | 2018-09-25 | 中国科学院大连化学物理研究所 | A kind of method that alcohol and 2- amino-benzylamines are synthetically prepared quinazoline derivant |
| CN104557737B (en) * | 2015-01-13 | 2016-12-14 | 王文明 | A kind of synthetic method of 2 aryl substituted quinazoline class medicine intermediates |
| CN105153045B (en) * | 2015-09-25 | 2017-12-19 | 温州医科大学附属第二医院 | A kind of synthetic method of pharmaceutical intermediate quinazoline derivant |
| CN106008370B (en) * | 2016-06-12 | 2018-12-18 | 温州大学 | A kind of synthetic method of 2- substituted quinazoline heterocyclic compounds |
| CN108424394B (en) * | 2018-03-12 | 2020-04-21 | 温州大学 | Synthetic method of nitrogen-containing heterocyclic drug intermediate |
| CN110606839B (en) * | 2019-09-30 | 2021-10-08 | 南方医科大学 | Green synthesis method of polysubstituted quinazoline derivative |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999042456A2 (en) * | 1998-02-18 | 1999-08-26 | Neurosearch A/S | Novel compounds and their use as positive ampa receptor modulators |
| CN102432551A (en) * | 2011-11-18 | 2012-05-02 | 成都理工大学 | Method for synthesizing 2-arylquinazolinethione |
| CN102675222A (en) * | 2012-04-28 | 2012-09-19 | 清华大学 | Method for preparing multi-substituted quinazoline and heterocyclic pyrimidine derivative |
-
2013
- 2013-06-04 CN CN201310219956.6A patent/CN103275016B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999042456A2 (en) * | 1998-02-18 | 1999-08-26 | Neurosearch A/S | Novel compounds and their use as positive ampa receptor modulators |
| CN102432551A (en) * | 2011-11-18 | 2012-05-02 | 成都理工大学 | Method for synthesizing 2-arylquinazolinethione |
| CN102675222A (en) * | 2012-04-28 | 2012-09-19 | 清华大学 | Method for preparing multi-substituted quinazoline and heterocyclic pyrimidine derivative |
Non-Patent Citations (1)
| Title |
|---|
| "Investigating the anti-proliferative activity of styrylazanaphthalenes and azanaphthalenediones";Anna Mrozek-Wilczkiewicz等;《Bioorganic & Medicinal Chemistry》;20100219;第18卷;第2664-2671页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103275016A (en) | 2013-09-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103275016B (en) | Synthetic method of 2-subsituted quinazoline compounds | |
| CN103467388B (en) | Method for synthesizing aryl or heteroaryl substituted quinazoline compound | |
| EP3398952B1 (en) | Synthesis process of ruxolitinib | |
| CN103435558B (en) | Synthetic method of quinazoline derivative | |
| JP7038263B2 (en) | Method for Producing Morpholine Quinazoline Compound and its Intermediate | |
| CN104529895A (en) | Synthetic method of nitrogen-containing heterocyclic compound | |
| CN108690015B (en) | A method of preparing Quinazol derivative | |
| CN107573336B (en) | Benzoheterocycle-formamide-pyridone derivative and preparation method and application thereof | |
| CN103554035B (en) | Preparation method of 4,6-dihalogenated pyridine-5-aldehyde | |
| CN110156672B (en) | Preparation method of semicarbazide compound and application of prepared compound | |
| CN104507948A (en) | Method for producing nitrogenated heterocyclic N-oxide compound | |
| KR100574350B1 (en) | Process for preparation of 2-aminopyridine derivatives | |
| CN111032650A (en) | Novel intermediate useful for synthesis of aminopyrimidine derivative, method for preparing same, and method for preparing aminopyrimidine derivative using same | |
| CN104507949A (en) | Method for producing nitrogen-containing heterocyclic compound of high purity | |
| CN104487445A (en) | Novel method for preparing 1-oxacephalosporin derivative | |
| CN104860880A (en) | Method for synthesizing 8-(nitro methyl) quinoline compounds | |
| CN109705140A (en) | A kind of synthetic method of pyrido [2,3-d] [1,3] oxazines derivative | |
| CN110028448A (en) | A kind of preparation method of 3- hydroxyl -2,3- dihydro-isoquinoline -1,4- dione compounds | |
| CN103275086B (en) | 6-substituted quinazoline and quinazolinone compound, its synthesis method and application | |
| WO2018099424A1 (en) | Preparation method of a pyridinone derivative and an intermediate thereof | |
| CN104016913B (en) | A kind of method preparing amide compound | |
| CN103435539B (en) | Synthetic method of substituted pyridine derivative | |
| CN103059025B (en) | A kind of preparation method of carbapenem bicyclic nucleus | |
| CN105153045A (en) | Synthesis method for medical intermediate quinazoline derivative | |
| CN102491985B (en) | Synthesis method for 6-amino-2,2-dimethyl-2H-pyridino-[3,2-b] [1,4] oxazine-3(4H)-ketone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C53 | Correction of patent for invention or patent application | ||
| CB02 | Change of applicant information |
Address after: 325027 Wenzhou college, Zhejiang, West Road, No. 109 Applicant after: THE SECOND HOSPITAL AFFILIATED TO WENZHOU MEDICAL COLLEGE Address before: 325027 Wenzhou college, Zhejiang, West Road, No. 109 Applicant before: No. 2 Hospital Atlached to Wenzhou Medical College |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: APPLICANT; FROM: NO. 2 HOSPITAL ATLACHED TO WENZHOU MEDICAL COLLEGE TO: THE SECOND HOSPITAL AFFILIATED TO WENZHOU MEDICALCOLLEGE |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150311 Termination date: 20190604 |