CN106749046B - One kind containing the 1,4- pentadiene -3- ketoxime ether derivative and preparation method thereof of 4 (3H)-quinazolinones - Google Patents
One kind containing the 1,4- pentadiene -3- ketoxime ether derivative and preparation method thereof of 4 (3H)-quinazolinones Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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Abstract
The invention discloses a kind of Isosorbide-5-Nitrae-pentadiene -3- ketoxime ether derivatives for containing 4 (3H)-quinazolinones, it is characterised in that: its general formula is as follows:Wherein, R1For phenyl, substituted-phenyl or replace aromatic heterocyclic；R2For phenyl, substituted-phenyl or replace aromatic heterocyclic；R3For more than one hydrogen atom, the methoxyl group contained on the 5 of 4 (3H)-quinazolinones, 6,7 or 8, nitro, methyl, trifluoromethyl or halogen atom.The compounds of this invention has higher therapeutic and protective effects to Cucumber Mosaic Virus (CMV) and tobacco mosaic virus disease (TMV), shows higher anti-phytoviral activity, can be used for preparing Antiphytoviral pesticide.
Description
Technical field
The present invention relates to chemical technology fields, relate in particular to a kind of pentadiene ketoxime ether for containing 4 (3H)-quinazolinones
The preparation method of analog derivative and its application in terms of Antiphytoviral.
Background technique
Every year, economic loss caused by crops are due to infection plant's virus is up to 600,000,000,000 dollars, therefore, effectively controls
There is very important meaning to the development of entire agricultural with the treatment viroses of plant.In numerous plant viruses, tobacco
Leaf disease has the characteristics that disease incidence height and prevention and treatment are difficult, is listed in one of most destructive plant virus.However, so far
All plant antiviral agents being commercialized are only 30~50% to the therapeutic activity of plant virus under 500 μ g/mL concentration,
Its suppression result is obviously unsatisfactory.Therefore, novel, efficient and environment amenable plant antiviral agent how is developed to remain unchanged
It is the significant challenge put in face of drug initiative worker.
Natural products and its bionic pesticide have environmentally friendly, action site uniqueness and highly selective feature, anti-
Increasingly important role is played in terms of controlling plant disease.Curcumin, as a kind of polyphenol compound in turmeric,
It is widely used as fragrance, food preservative, monosodium glutamate and dyestuff.Isosorbide-5-Nitrae-pentadiene ketone compounds, as a kind of important ginger
Flavin derivatives, because its have desinsection, antibacterial, Antiphytoviral, anticancer, anti-inflammatory and the more wide spectrum such as anti-oxidant biology
Activity has been increasingly becoming one of the hot spot in medicament initiative field.In particular, relevant report in recent years shows Isosorbide-5-Nitrae-pentadiene-
3- ketone compounds possess extremely good anti-phytoviral activity.Therefore, based on such compound, its structure is carried out
Transformation, it is most likely that obtain the organic active molecule with excellent anti-phytoviral activity.
(the conjunction of Chou Qiujuan, Xue Wei, Lu Ping, Wang Zhenchao, Wei Xue the curcumin derivate of esters containing oxime such as Juan of enemy autumn in 2011
At and its antiviral activity [J] synthesis chemistry, 2011,19 (1): 36-40.) using bioactie agent splicing method by oxime ester knot
Structure is introduced into single carbonyl curcumin derivative 1, in the skeleton of 5- substituted-phenyl-Isosorbide-5-Nitrae-pentadiene -3- ketone, synthesized it is a series of not
Symmetrical 1,5- disubstituted aryl-Isosorbide-5-Nitrae-pentadiene -3- ketoxime class ester curcumin derivate, and anti-cucumber mosaic virus has been carried out to it
The active testing of poison.Test result shows: in the drug concentration of 500 μ g/mL, synthesized target compound is to cucumber mosaic
Virus has certain inhibiting effect, but is below its comparison medicament Ningnanmycin.
(Luo, the H. such as Luo in 2013；Liu,J.；Jin,L.；Hu,D.；Chen,Z.；Yang,S.；Wu,J.；Song,
B.Synthesis and antiviral bioactivity of novel(1E,4E)-1-aryl-5-(2-
(quinazolin-4-yloxy)phenyl)-1,4-pentadien-3-one derivatives[J].
Eur.J.Med.Chem., 2013,63:662-669.) quinazoline structure is introduced into 1,5- diaryl -1,4- pentadiene -3- ketone
Skeleton in, synthesized a series of (1E, 4E) -1- aryl -5- (2- (4- oxoquinazolin) phenyl)-Isosorbide-5-Nitrae-pentadiene -3- ketone
Class compound, and the active testing of resisting tobacco mosaic virus and anti cucumber mosaic virus has been carried out to it.Test result shows: should
Series compound has the protective effect of significant ground to tobacco mosaic virus (TMV), wherein there is part of compounds in terms of protective effect to cigarette
The EC of showy flowers of herbaceous plants mosaic virus50Value is better than its comparison medicament Ningnanmycin.
(Ma, the J. such as Ma in 2014；Li,P.；Li,X.；Shi,Q.；Wan,Z.；Hu,D.；Jin,L.；Song,
B.Synthesis and Antiviral Bioactivity of Novel3-((2-((1E,4E)-3-oxo-5-
arylpenta-1,4-dien-1-yl)phenoxy)methyl)-4(3H)-quinazolinone Derivatives[J]
.J.Agric.Food Chem., 2014,62,8928-8934.) 4 (3H)-quinazolinone structures are introduced into 1,5- diaryl-
In Isosorbide-5-Nitrae-pentadiene -3- ketone skeleton, a series of pentadiene ketone compounds of Quinazolinone-containings are synthesized, and carry out to it
The active testing of anti-TMV.Test result shows: when drug concentration is 500 μ g/mL, compound synthesized by major part is to TMV
There are certain living body inhibition and healing effect.Wherein there is effect of the part of compounds in terms of living body treatment fabulous, inhibits
Rate is better than its comparison medicament Ningnanmycin.
(Chen, the M. such as Chen in 2015；Hu,D.；Li,X.；Yang,S.；Zhang,W.；Li,P.；Song,
B.Antiviral activity and interaction mechanisms study of novel
Glucopyranoside derivatives [J] .Bioorg.Med.Chem.Lett., 2015,25:3840-3844.) in order to
New and effective and less toxic anti-plant virus agent is formulated, based on curcumin, principle is spliced using active group, will naturally be lived
Property ingredient pyranoside is introduced into pentadienone structure, has synthesized a series of pentadiene ketone compounds containing pyranoside, and
Using half leaf withered spot method, using virazole as comparison medicament, the passivation activity of the anti-TMV of target compound is tested.Test result
Show: synthesized compound has certain passivation activity to TMV, wherein have the passivation effect of part of compounds preferable,
EC50Value is superior to its comparison medicament virazole.Preliminary mechanism study shows: such compound mainly by with TMV shell egg
White independence in conjunction with and make its passivation inactivation.
(Han, the Y. such as Han in 2015；Ding,Y.；Xie,D.；Hu,D.；Li,P.；Li,X.；Xue,W.；Jin,L.；
Song,B.Design,synthesis and antiviral activity of novel rutin derivatives
Containing 1,4-pentadien-3-one moiety [J] .Eur.J.Med.Chem., 2015,92:732-737.) it will
Isolated rutin is introduced into the skeleton of 1,5- diaryl-Isosorbide-5-Nitrae-pentadiene -3- ketone in stalwart wormwood artemisia, has synthesized a series of molecules
In containing Isosorbide-5-Nitrae-pentadiene -3- ketone structure novel rutin class compound, and it has been carried out anti-TMV and anti-CMV activity survey
Examination.Test result shows: when drug concentration is 500 μ g/mL, the compound largely synthesized has certain anti-TMV and resists
The activity of CMV.Wherein there is the therapeutic activity of the anti-CMV of part of compounds best, EC50Value is mould better than its comparison medicament Ningnan
Element.
(Long, the C. such as Long in 2015；Li,P.；Chen,M.；Dong,L.；Hu,D.；Song,B.Synthesis,
anti-tobacco mosaic virus and curcumber mosaic virus activity,and3D-QSAR
study of novel 1,4-pentadien-3-one derivatives containing4-thioquinazoline
Moiety [J] .Eur.J.Med.Chem., 2015,102:639-647.) thio quinazoline is introduced into 1,5- diaryl -1,4-
In the skeleton of pentadiene -3- ketone, a series of pentadiene ketone compounds replaced in molecules containing quinazoline thioether have been synthesized, and
The active testing of anti-TMV and anti-CMV have been carried out to it.Test result shows: when drug concentration is 500 μ g/mL, the change of synthesis
Close the activity that object has certain anti-TMV and anti-CMV.Part of compound is to TMV and CMV in terms of therapeutic and protective effects
With excellent inhibitory activity, EC50Value is better than comparison medicament Ningnanmycin.
(Gan, the X. such as Gan in 2016；Hu,D.；Li,P.；Wu,J.；Chen,X.；Xue,W.；Song,B.Design,
synthesis,antiviral activity and three-dimentional quantitative structure-
activity relationship study of novel 1,4-pentadien-3-one derivatives
Containing 1,3,4-oxadiazole moiety [J] .Pest Manag.Sci., 2016,72:534-543.) by 1,3,
4- oxadiazoles structure is introduced into the skeleton of 1,5- diaryl-Isosorbide-5-Nitrae-pentadiene -3- ketone, has been synthesized in a series of molecules and has been contained 1,
The pentadiene ketone compounds of 3,4- oxadiazoles thio ethoxies, and anti-TMV active testing has been carried out to it.Test result table
Bright: when drug concentration is 500 μ g/mL, the compound of synthesis has the activity of preferable anti-TMV.Part of compound exists
There is excellent activity, EC in terms of anti-TMV protection activity50Value is much better than its comparison medicament virazole.
Quianzolinones, as a kind of important heterocycle compound, because it in variability and has in structure
More the bioactivity of broad-spectrum high efficacy and become medicament initiative field in hot spot.Recent studies indicate that: such compound
There is relatively broad prospect in terms of Antiphytoviral.
(Gao, the X. such as Gao in 2007；Cai,X.；Yan,K.；Song,B.；Gao,L.；Chen,Z.Synthesis and
antiviral bioactivities of2-phenyl-3-(substituted-benzalamino)-4(3H)-
Quinazolinone derivatives [J] .Molecules, 2007,12:2621-2642.) design synthesized and a series of contained 4
The Schiff class compound of (3H)-quinazolinone structure, and the active testing of anti-TMV has been carried out to it.Test result shows:
When drug concentration is 500 μ g/mL, compound synthesized by major part has certain living body inhibiting effect to TMV.
(Ma, the J. such as Ma in 2014；Li,P.；Li,X.；Shi,Q.；Wan,Z.；Hu,D.；Jin,L.；Song,
B.Synthesis and Antiviral Bioactivity of Novel3-((2-((1E,4E)-3-oxo-5-
arylpenta-1,4-dien-1-yl)phenoxy)methyl)-4(3H)-quinazolinone Derivatives[J]
.J.Agric.Food Chem., 2014,62,8928-8934.) 4 (3H)-quinazolinone structures are introduced into 1,5- diaryl-
In Isosorbide-5-Nitrae-pentadiene -3- ketone skeleton, a series of pentadiene ketone compounds of Quinazolinone-containings are synthesized, and carry out to it
The active testing of anti-TMV.Test result shows: when drug concentration is 500 μ g/mL, compound synthesized by major part is to TMV
There are certain living body inhibition and healing effect.Effect of part of compound in terms of living body treatment is fabulous, inhibiting rate
Better than its comparison medicament Ningnanmycin.
(Chen, the M. such as Chen in 2016；Li,P.；Hu,D.；Zeng,S.；Li,T.；Jin,L.；Xue,W.；Song,
B.Synthesis,antiviral activity,3D-QSAR,and interaction mechanisms study of
novel malonate derivatives containing quinazolin-4(3H)-4-one moitey[J]
.Bioorg.Med.Chem.Lett., 2016,26:168-173.) 4 (3H)-quinazolinone structures are effectively tied with malonate
It closes, design has synthesized a series of quianzolinones in molecules containing malonate, and the activity of anti-CMV has been carried out to it
Test.Test result shows: when drug concentration is 500 μ g/mL, compound synthesized by major part has CMV certain
Living body inhibiting effect.Effect of part of compound in terms of living body treatment is fabulous, and inhibiting rate is peaceful better than its comparison medicament
Southern mycin.
In conclusion Isosorbide-5-Nitrae-pentadiene -3- ketone compounds and 4 (3H)-quianzolinones are in Antiphytoviral
Aspect has certain researching value, but the compound with antiviral activity currently formulated out is being protected and controlled not yet
Treat two aspects of activity is more than Ningnanmycin simultaneously, while also be there are no about the Isosorbide-5-Nitrae-penta two for containing 4 (3H)-quinazolinones
Report in terms of the synthesis of alkene -3- ketoxime ether compound and anti-phytoviral activity.
Summary of the invention
The technical problem to be solved by the present invention is providing the pentadiene ketoxime ether for containing 4 (3H)-quinazolinones in a kind of structure
Class compound and preparation method thereof prevents and treats effect to solve antiviral activity compound in the prior art in terms of preventing and treating plant virus
The bad technical problem of fruit.
The technical scheme is that a kind of Isosorbide-5-Nitrae-pentadiene -3- ketoxime ether derivative for containing 4 (3H)-quinazolinones,
Its general formula is as follows:
Wherein, R1For phenyl, substituted-phenyl or replace aromatic heterocyclic；R2For phenyl, substituted-phenyl or replace virtue
Heterocycle；R3For the more than one hydrogen original contained on the 5 of 4 (3H)-quinazolinones, 6,7 or 8
Son, methoxyl group, nitro, methyl, trifluoromethyl or halogen atom.
The substituted-phenyl be on phenyl ring it is o-, m-, pair or aforementioned two upper contain more than one methoxyl group, nitro, first
Base, trifluoromethyl or halogen atom；The substitution aromatic heterocyclic is furyl, pyridyl group, thienyl, pyrrole radicals, thiazolyl, 2-
Chloropyridine base or 2- diuril oxazolyl.
One kind containing Isosorbide-5-Nitrae-pentadiene -3- ketoxime ether derivative preparation method of 4 (3H)-quinazolinones, containing substitution
3- (chloromethyl) quinazoline -4 (3H) ketone and 1- (4- (substituted benzyloxy) phenyl) -5- substituted aryl -1,4- the pentadiene -3- of base
Ketoxime or 1- (2- (substituted benzyloxy) phenyl) -5- substituted aryl -1,4- pentadiene -3- ketoxime are that raw material preparation contains 4 (3H)-quinolines
1,4- pentadiene -3- ketoxime ether the derivative of oxazoline ketone:
(2- (replaces by 1- (4- (substituted benzyloxy) the phenyl) -5- substituted aryl -1,4- pentadiene -3- ketoxime or 1-
Benzyloxy) phenyl) -5- substituted aryl -1,4- pentadiene -3- ketoxime the preparation method comprises the following steps: (1) with acetone, salicylide or 4- hydroxyl
Benzaldehyde is raw material, prepares 2- (hydroxy phenyl)-3- butene-2 -one or 4- (hydroxy phenyl)-3- butylene-under alkaline condition
2- ketone:
(2) it is with substituted aroma aldehyde, 2- (hydroxy phenyl)-3- butene-2 -one or 4- (hydroxy phenyl)-3- butene-2 -one
Raw material prepares 1- substituted aryl -5- (4- hydroxy phenyl)-Isosorbide-5-Nitrae-pentadiene -3- ketone or 1- substituted aryl -5- under alkaline condition
(2- hydroxy phenyl) -1,4- pentadiene -3- ketone:
(3) to replace benzyl chloride, 1- substituted aryl -5- (4- hydroxy phenyl) -1,4- pentadiene -3- ketone or 1- substituted aryl -
5- (2- hydroxy phenyl)-1,4- pentadiene-3- ketone is that raw material prepares 1- (4- (substituted benzyloxy) phenyl) substituted aryl-1-5-,
4- pentadiene -3- ketone or 1- (2- (substituted benzyloxy) phenyl) -5- substituted aryl -1,4- pentadiene -3- ketone:
(4) with hydroxylamine hydrochloride, 1- (4- (substituted benzyloxy) phenyl) -5- substituted aryl -1,4- pentadiene -3- ketone or 1-
(2- (substituted benzyloxy) phenyl) -5- substituted aryl -1,4- pentadiene -3- ketone is that raw material prepares 1- (4- (substituted benzyloxy) benzene
Base) -5- substituted aryl -1,4- pentadiene -3- ketoxime or 1- (2- (substituted benzyloxy) phenyl) -5- substituted aryl -1,4- penta 2
Alkene -3- ketoxime:
Described 3- (chloromethyl) quinazoline -4 (3H) ketone containing substituent group the preparation method comprises the following steps: (1) containing substituent group
(3H) ketone of quinazoline -4 and formaldehyde are that raw material prepares 3- (hydroxymethyl) quinazoline -4 (3H) ketone containing substituent group:
(2) using containing substituent group -4 (3H) ketone of 3- hydroxymethyl quinazoline and thionyl chloride be raw material prepare containing substituent group
3- (chloromethyl) quinazoline -4 (3H) ketone:
Beneficial effects of the present invention: 4 (3H)-quinazolinone structures with excellent activity are introduced pentadienone by the present invention
In the structure of oxime ether, design has synthesized a series of pentadienone oximido ether compound for containing 4 (3H)-quinazolinones in structures,
And the synthesized 1,4- pentadiene -3- ketoxime ether compound containing 4 (3H)-quinazolinones is applied to Antiphytoviral aspect
Research, find such compound than currently existing compound (cucumber mosaic virus and Tobacco mosaic in terms of Antiphytoviral
Virus) possess activity more outstanding, suppression of part of compound in terms for the treatment of with protection activity to tobacco mosaic virus (TMV)
System activity is more than its comparison medicament Ningnanmycin, has certain application value.
Specific embodiment
Total embodiment:
(1) using acetone, salicylide or 4- hydroxy benzaldehyde as raw material, 2- (hydroxy phenyl) -3- is prepared under alkaline condition
Butene-2 -one or 4- (hydroxy phenyl)-3- butene-2 -one:
(2) it is with substituted aroma aldehyde, 2- (hydroxy phenyl)-3- butene-2 -one or 4- (hydroxy phenyl)-3- butene-2 -one
Raw material prepares 1- substituted aryl -5- (4- hydroxy phenyl)-Isosorbide-5-Nitrae-pentadiene -3- ketone or 1- substituted aryl -5- under alkaline condition
(2- hydroxy phenyl) -1,4- pentadiene -3- ketone:
(3) to replace benzyl chloride, 1- substituted aryl -5- (4- hydroxy phenyl) -1,4- pentadiene -3- ketone or 1- substituted aryl -
5- (2- hydroxy phenyl)-1,4- pentadiene-3- ketone is that raw material prepares 1- (4- (substituted benzyloxy) phenyl) substituted aryl-1-5-,
4- pentadiene -3- ketone or 1- (2- (substituted benzyloxy) phenyl) -5- substituted aryl -1,4- pentadiene -3- ketone:
(4) with hydroxylamine hydrochloride, 1- (4- (substituted benzyloxy) phenyl) -5- substituted aryl -1,4- pentadiene -3- ketone or 1-
(2- (substituted benzyloxy) phenyl) -5- substituted aryl -1,4- pentadiene -3- ketone is that raw material prepares 1- (4- (substituted benzyloxy) benzene
Base) -5- substituted aryl -1,4- pentadiene -3- ketoxime or 1- (2- (substituted benzyloxy) phenyl) -5- substituted aryl -1,4- penta 2
Alkene -3- ketoxime:
(5) using containing substituent group (3H) ketone of quinazoline -4 and formaldehyde as raw material prepare 3- (hydroxymethyl) quinoline containing substituent group
Oxazoline -4 (3H) ketone；
(6) using containing substituent group -4 (3H) ketone of 3- hydroxymethyl quinazoline and thionyl chloride be raw material prepare containing substituent group
3- (chloromethyl) quinazoline -4 (3H) ketone:
(7) with containing substituent group 3- (chloromethyl) quinazoline -4 (3H) ketone and 1- (4- (substituted benzyloxy) phenyl) -5- take
For aryl -1,4- pentadiene -3- ketoxime or 1- (2- (substituted benzyloxy) phenyl) -5- substituted aryl -1,4- pentadiene -3- ketoxime
Contain the 1,4- pentadiene -3- ketoxime ether derivative of 4 (3H)-quinazolinones for raw material preparation:
Specific embodiment is listed in a manner of list below, see the table below:
Embodiment 1
(3- (4 (3H)-quinazolinone)) methyl-1-(4- (3- benzyl chloride oxygroup) phenyl)-5- (2- pyridyl group)-1,4- penta 2
Synthesis (the compound number I of alkene -3- ketoxime ether1), comprising the following steps:
(1) synthesis of 4- (hydroxy phenyl)-3- butene-2 -one:
4- hydroxy benzaldehyde (6.1g, 50mmol) is added in the acetone of 60mL, after stir about 15min, this is anti-for ice bath
After answering system about 30min, 5% NaOH solution of about 100mL is added into system, after being added dropwise, removes ice bath room, often
Warm stir about is for 24 hours.To after reaction, system is transferred in the beaker of 500mL and appropriate ice water is added, then with 5%
After dilute hydrochloric acid solution regulation system pH is about 5~6, there are a large amount of yellow solids to be precipitated, solid is extracted out, finally uses ethanol/water body
System's recrystallization is to get 5.30g yellow solid (Theoretical Mass 8.10g), yield 65%.
(2) synthesis of 1- (2- pyridyl group) -5- (4- hydroxy phenyl) -1,4- pentadiene -3- ketone:
By 4- (hydroxy phenyl)-3- butene-2 -one (4.0g, 24.7mmol), pyridine-2-formaldehyde (2.86mL,
29.6mmol) it is added in the three-necked flask of 250mL with 50mL ethyl alcohol, after stir about 30min, the 5% of 60mL into system
NaOH solution removes ice bath room, stirring at normal temperature is about for 24 hours after being added dropwise.To after reaction, system is transferred to 500mL
Beaker in and appropriate ice water is added, after being about then 5~6 with 5% dilute hydrochloric acid solution regulation system pH, have a large amount of yellow solid
Body is precipitated, and solid is extracted out to get 4.96g yellow solid (theoretical yield 6.20g), yield 80%.
(3) synthesis of 1- (4- (3- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketone:
1- (2- pyridyl group) -5- (4- hydroxy phenyl) -1,4- pentadiene -3- is sequentially added in the three-necked flask of 100mL
Ketone (2.50g, 9.95mmol), methyl benzyl chloride (1.71g, 11.94mmol), potassium carbonate (2.06g, 14.92mmol), potassium iodide
(0.83g, 4.97mmol) and acetone (60mL), it is to be mixed uniformly after be heated to reflux, after about 3~4h reaction terminate, remove molten, column layer
Analysis, obtains 1.25g yellow solid (theoretical yield 3.21g), yield 39%.
(4) synthesis of 1- (4- (3- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketoxime:
1- (4- (3- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group) -1,4- penta 2 is sequentially added in the there-necked flask of 100mL
Alkene -3- ketone (3.00g, 8.44mmol), hydroxylamine hydrochloride (1.76g, 25.32mmol), pyridine (25mL) and ethyl alcohol (50mL), room temperature
Stir about for 24 hours after, have white solid precipitation in system, this solid extracted out, ethanol rinse is (theoretical to get white solid 1.87g
Yield 3.12g), yield 60%.
(5) synthesis of 3- (hydroxymethyl) quinazoline -4 (3H) ketone:
Quinazoline -4 (3H) ketone (3.00g, 20.53mmol), formalin are sequentially added in the there-necked flask of 100mL
(30mL) and Isosorbide-5-Nitrae-dioxane (40mL), it is to be mixed uniformly after, being heated to reflux after 3~4h to react terminates.Then rapidly by body
System is transferred in the beaker of 500mL, generates a large amount of white solids after suitable quantity of water dispersion is added, filters, obtain white solid 2.94g
(theoretical yield 3.63g), yield 81%.
(6) synthesis of 3- (chloromethyl) quinazoline -4 (3H) ketone:
Sequentially added in the there-necked flask of 100mL 3- (hydroxymethyl) quinazoline -4 (3H) ketone (3.00g, 17.03mmol),
Thionyl chloride (30mL) and Isosorbide-5-Nitrae-dioxane (40mL), it is to be mixed uniformly after, being heated to reflux after 3~4h to react terminates.Then
System is transferred in the beaker of 500mL rapidly and is extracted with after concentrated sodium hydroxide regulation system to strong basicity, then with methylene chloride
It takes 3 times, merges organic phase, go molten to get white solid 2.00g (theoretical yield 3.33g), yield 60%.
(7) (3- (4 (3H)-quinazolinone)) methyl-1-(4- (3- benzyl chloride oxygroup) phenyl)-5- (2- pyridyl group)-1,4-
The synthesis of pentadiene -3- ketoxime ether:
1- (4- (3- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group) -1,4- penta 2 is sequentially added in the there-necked flask of 50mL
Alkene -3- ketoxime (0.50g, 1.28mmol), 3- (chloromethyl) quinazoline -4 (3H) ketone (0.30g, 1.54mmol), potassium carbonate
(0.35g, 2.56mmol) and acetonitrile (35mL), it is to be mixed uniformly after, being heated to reflux after 3~4h to react terminates.System mistake while hot
Filter, filtrate are gone molten, are then recrystallized with acetonitrile (35mL × 3) to get white needle-like crystals 0.25g (theoretical yield 0.69g), are produced
Rate 36%.
Embodiment 2
(3- (4 (3H)-quinazolinone)) methyl-1-(4- (2- benzyl chloride oxygroup) phenyl)-5- (3- pyridyl group)-1,4- penta 2
Synthesis (the compound number I of alkene -3- ketoxime ether2), comprising the following steps:
(1) synthesis of 4- (hydroxy phenyl)-3- butene-2 -one:
Such as 1 (1) step of embodiment.
(2) synthesis of 1- (3- pyridyl group) -5- (4- hydroxy phenyl) -1,4- pentadiene -3- ketone:
Such as 1 (2) step of embodiment, difference is using pyridine -3- formaldehyde as raw material.
(3) synthesis of 1- (4- (2- benzyl chloride oxygroup) phenyl) -5- (3- pyridyl group) -1,4- pentadiene -3- ketone:
Such as 1 (3) step of embodiment, difference is with 1- (3- pyridyl group) -5- (4- hydroxy phenyl)-Isosorbide-5-Nitrae-pentadiene -3-
Ketone and o-chloro benzyl chloride are raw material.
(4) synthesis of 1- (4- (2- benzyl chloride oxygroup) phenyl) -5- (3- pyridyl group) -1,4- pentadiene -3- ketoxime:
Such as 1 (4) step of embodiment, difference is with 1- (4- (2- benzyl chloride oxygroup) phenyl) -5- (3- pyridyl group)-Isosorbide-5-Nitrae-penta
Diene -3- ketone is raw material.
(5) synthesis of 3- (hydroxymethyl) quinazoline -4 (3H) ketone:
Such as 1 (5) step of embodiment.
(6) synthesis of 3- (chloromethyl) quinazoline -4 (3H) ketone:
Such as 1 (6) step of embodiment.
(7) (3- (4 (3H)-quinazolinone)) methyl-1-(4- (2- benzyl chloride oxygroup) phenyl)-5- (3- pyridyl group)-1,4-
The synthesis of pentadiene -3- ketoxime ether:
Such as 1 (7) step of embodiment, difference is with 1- (4- (2- benzyl chloride oxygroup) phenyl) -5- (3- pyridyl group)-Isosorbide-5-Nitrae-penta
Diene -3- ketoxime is raw material.
Embodiment 3
(3- (4 (3H)-quinazolinone)) methyl-1-(4- (3- methylbenzyloxy) phenyl)-5- (2- pyridyl group)-1,4- penta
Synthesis (the compound number I of diene -3- ketoxime ether3), comprising the following steps:
(1) synthesis of 4- (hydroxy phenyl)-3- butene-2 -one:
Such as 1 (1) step of embodiment.
(2) synthesis of 1- (2- pyridyl group) -5- (4- hydroxy phenyl) -1,4- pentadiene -3- ketone:
Such as 1 (2) step of embodiment.
(3) synthesis of 1- (4- (3- methylbenzyloxy) phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketone:
Such as 1 (3) step of embodiment, difference is using methyl benzyl chloride as raw material.
(4) synthesis of 1- (4- (3- methylbenzyloxy) phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketoxime:
Such as 1 (4) step of embodiment, difference is with 1- (4- (3- methylbenzyloxy) phenyl) -5- (2- pyridyl group)-Isosorbide-5-Nitrae -
Pentadiene -3- ketone is raw material.
(5) synthesis of 3- (hydroxymethyl) quinazoline -4 (3H) ketone:
Such as 1 (5) step of embodiment.
(6) synthesis of 3- (chloromethyl) quinazoline -4 (3H) ketone:
Such as 1 (6) step of embodiment.
(7) (3- (4 (3H)-quinazolinone)) methyl-1-(4- (3- methylbenzyloxy) phenyl)-5- (2- pyridyl group)-1,
The synthesis of 4- pentadiene -3- ketoxime ether:
Such as 1 (7) step of embodiment, difference is with 1- (4- (3- methylbenzyloxy) phenyl) -5- (2- pyridyl group)-Isosorbide-5-Nitrae -
Pentadiene -3- ketoxime is raw material.
Embodiment 4
(3- (4 (3H)-quinazolinone)) methyl-1-(2- (2- benzyl chloride oxygroup) phenyl)-5- (2- pyridyl group)-1,4- penta 2
Synthesis (the compound number I of alkene -3- ketoxime ether4), comprising the following steps:
(1) synthesis of 2- (hydroxy phenyl)-3- butene-2 -one:
Such as 1 (1) step of embodiment, difference is using salicylide as raw material.
(2) synthesis of 1- (2- pyridyl group) -5- (2- hydroxy phenyl) -1,4- pentadiene -3- ketone:
Such as 1 (2) step of embodiment, difference is using 2- (hydroxy phenyl)-3- butene-2 -one as raw material.
(3) synthesis of 1- (2- (2- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketone:
Such as 1 (3) step of embodiment, difference is with o-chloro benzyl chloride and 1- (2- pyridyl group) -5- (2- hydroxy phenyl)-Isosorbide-5-Nitrae -
Pentadiene -3- ketone is raw material.
(4) synthesis of 1- (2- (2- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketoxime:
Such as 1 (4) step of embodiment, difference is with 1- (2- (2- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group)-Isosorbide-5-Nitrae-penta
Diene -3- ketone is raw material.
(5) synthesis of 3- (hydroxymethyl) quinazoline -4 (3H) ketone:
Such as 1 (5) step of embodiment.
(6) synthesis of 3- (chloromethyl) quinazoline -4 (3H) ketone:
Such as 1 (6) step of embodiment.
(7) (3- (4 (3H)-quinazolinone)) methyl-1-(2- (2- benzyl chloride oxygroup) phenyl)-5- (2- pyridyl group)-1,4-
The synthesis of pentadiene -3- ketoxime ether:
Such as 1 (7) step of embodiment, difference is with 1- (2- (2- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group)-Isosorbide-5-Nitrae-penta
Diene -3- ketoxime is raw material.
Embodiment 5
(3- (4 (3H)-quinazolinone)) methyl-1-(4- (2- benzyl chloride oxygroup) phenyl)-5- (2- pyridyl group)-1,4- penta 2
Synthesis (the compound number I of alkene -3- ketoxime ether5), comprising the following steps:
(1) synthesis of 4- (hydroxy phenyl)-3- butene-2 -one:
Such as 1 (1) step of embodiment.
(2) synthesis of 1- (4- hydroxy phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketone:
Such as 1 (2) step of embodiment.
(3) synthesis of 1- (4- (2- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketone:
Such as 1 (3) step of embodiment, difference is using o-chloro benzyl chloride as raw material.
(4) synthesis of 1- (4- (2- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketoxime:
Such as 1 (4) step of embodiment, difference is with 1- (4- (2- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group)-Isosorbide-5-Nitrae-penta
Diene -3- ketone is raw material.
(5) synthesis of 3- (hydroxymethyl) quinazoline -4 (3H) ketone:
Such as 1 (5) step of embodiment.
(6) synthesis of 3- (chloromethyl) quinazoline -4 (3H) ketone:
Such as 1 (6) step of embodiment.
(7) (3- (4 (3H)-quinazolinone)) methyl-1-(4- (2- benzyl chloride oxygroup) phenyl)-5- (2- pyridyl group)-1,4-
The synthesis of pentadiene -3- ketoxime ether:
Such as 1 (7) step of embodiment, difference is with 1- (4- (2- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group)-Isosorbide-5-Nitrae-penta
Diene -3- ketoxime is raw material.
Embodiment 6
(3- (4 (3H)-quinazolinone)) methyl-1-(2- (2,4- dichloro-benzyloxy) phenyl)-5- (2- pyridyl group)-1,4-
Synthesis (the compound number I of pentadiene -3- ketoxime ether6), comprising the following steps:
(1) synthesis of 2- (hydroxy phenyl)-3- butene-2 -one:
Such as 1 (1) step of embodiment, difference is using salicylide as raw material.
(2) synthesis of 1- (2- hydroxy phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketone:
Such as 1 (2) step of embodiment, difference is using 2- (hydroxy phenyl)-3- butene-2 -one as raw material.
(3) synthesis of 1- (2- (2,4- dichloro-benzyloxy) phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketone:
Such as 1 (3) step of embodiment, difference is with 1- (2- hydroxy phenyl) -5- (2- pyridyl group)-Isosorbide-5-Nitrae-pentadiene -3-
Ketone and 2,4- dichloro benzyl chloride are raw material.
(4) synthesis of 1- (2- (2,4- dichloro-benzyloxy) phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketoxime:
Such as 1 (4) step of embodiment, difference is with 1- (2- (2,4- dichloro-benzyloxy) phenyl) -5- (2- pyridyl group) -1,
4- pentadiene -3- ketone is raw material.
(5) synthesis of 3- (hydroxymethyl) quinazoline -4 (3H) ketone:
Such as 1 (5) step of embodiment.
(6) synthesis of 3- (chloromethyl) quinazoline -4 (3H) ketone:
Such as 1 (6) step of embodiment.
(7) (3- (4 (3H)-quinazolinone)) methyl-1-(2- (2,4- dichloro-benzyloxy) phenyl)-5- (2- pyridyl group)-
The synthesis of 1,4- pentadiene -3- ketoxime ether:
Such as 1 (7) step of embodiment, difference is with 1- (2- (2,4- dichloro-benzyloxy) phenyl) -5- (2- pyridyl group) -1,
4- pentadiene -3- ketoxime is raw material.
Embodiment 7
(3- (4 (3H)-quinazolinone)) methyl-1-(4- (4- benzyl chloride oxygroup) phenyl)-5- (2- pyridyl group)-1,4- penta 2
Synthesis (the compound number I of alkene -3- ketoxime ether7), comprising the following steps:
(1) synthesis of 4- (hydroxy phenyl)-3- butene-2 -one:
Such as 1 (1) step of embodiment.
(2) synthesis of 1- (4- hydroxy phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketone:
Such as 1 (2) step of embodiment.
(3) synthesis of 1- (4- (4- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketone:
Such as 1 (3) step of embodiment, difference be using to benzyl chloride chlorine as raw material.
(4) synthesis of 1- (4- (4- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketoxime:
Such as 1 (4) step of embodiment, difference is with 1- (4- (4- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group)-Isosorbide-5-Nitrae-penta
Diene -3- ketone is raw material.
(5) synthesis of 3- (hydroxymethyl) quinazoline -4 (3H) ketone:
Such as 1 (5) step of embodiment.
(6) synthesis of 3- (chloromethyl) quinazoline -4 (3H) ketone:
Such as 1 (6) step of embodiment.
(7) (3- (4 (3H)-quinazolinone)) methyl-1-(4- (4- benzyl chloride oxygroup) phenyl)-5- (2- pyridyl group)-1,4-
The synthesis of pentadiene -3- ketoxime ether:
Such as 1 (7) step of embodiment, difference is with 1- (4- (4- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group)-Isosorbide-5-Nitrae-penta
Diene -3- ketoxime is raw material.
Embodiment 8
(3- (4 (3H)-quinazolinone)) methyl-1-(4- (4- benzyl chloride oxygroup) phenyl)-5- (2- thienyl)-1,4- penta 2
Synthesis (the compound number I of alkene -3- ketoxime ether8), comprising the following steps:
(1) synthesis of 4- (hydroxy phenyl)-3- butene-2 -one:
Such as 1 (1) step of embodiment.
(2) synthesis of 1- (4- hydroxy phenyl) -5- (2- thienyl) -1,4- pentadiene -3- ketone:
Such as 1 (2) step of embodiment, difference is using 2 thiophene carboxaldehyde as raw material.
(3) synthesis of 1- (4- (4- benzyl chloride oxygroup) phenyl) -5- (2- thienyl) -1,4- pentadiene -3- ketone:
Such as 1 (3) step of embodiment, difference is to benzyl chloride chlorine and 1- (4- hydroxy phenyl) -5- (2- thienyl)-Isosorbide-5-Nitrae -
Pentadiene -3- ketone is raw material.
(4) synthesis of 1- (4- (4- benzyl chloride oxygroup) phenyl) -5- (2- thienyl) -1,4- pentadiene -3- ketoxime:
Such as 1 (4) step of embodiment, difference is with 1- (4- (4- benzyl chloride oxygroup) phenyl) -5- (2- thienyl)-Isosorbide-5-Nitrae-penta
Diene -3- ketone is raw material.
(5) synthesis of 3- (hydroxymethyl) quinazoline -4 (3H) ketone:
Such as 1 (5) step of embodiment.
(6) synthesis of 3- (chloromethyl) quinazoline -4 (3H) ketone:
Such as 1 (6) step of embodiment.
(7) (3- (4 (3H)-quinazolinone)) methyl-1-(4- (4- benzyl chloride oxygroup) phenyl)-5- (2- thienyl)-1,4-
The synthesis of pentadiene -3- ketoxime ether:
Such as 1 (7) step of embodiment, difference is with 1- (4- (4- benzyl chloride oxygroup) phenyl) -5- (2- thienyl)-Isosorbide-5-Nitrae-penta
Diene -3- ketoxime is raw material.
Embodiment 9
(3- (4 (3H)-quinazolinone)) methyl-1-(4- (2,4- dichloro-benzyloxy) phenyl)-5- (2- thienyl)-1,4-
Synthesis (the compound number I of pentadiene -3- ketoxime ether9), comprising the following steps:
(1) synthesis of 4- (hydroxy phenyl)-3- butene-2 -one:
Such as 1 (1) step of embodiment.
(2) synthesis of 1- (4- hydroxy phenyl) -5- (2- thienyl) -1,4- pentadiene -3- ketone:
Such as 1 (2) step of embodiment, difference is using 2 thiophene carboxaldehyde as raw material.
(3) synthesis of 1- (4- (2,4- dichloro-benzyloxy) phenyl) -5- (2- thienyl) -1,4- pentadiene -3- ketone:
Such as 1 (3) step of embodiment, difference is to 2,4- dichloro benzyl chloride and 1- (4- hydroxy phenyl) -5- (2- thiophene
Base) -1,4- pentadiene -3- ketone be raw material.
(4) synthesis of 1- (4- (2,4- dichloro-benzyloxy) phenyl) -5- (2- thienyl) -1,4- pentadiene -3- ketoxime:
Such as 1 (4) step of embodiment, difference is with 1- (4- (2,4- dichloro-benzyloxy) phenyl) -5- (2- thienyl) -1,
4- pentadiene -3- ketone is raw material.
(5) synthesis of 3- (hydroxymethyl) quinazoline -4 (3H) ketone:
Such as 1 (5) step of embodiment.
(6) synthesis of 3- (chloromethyl) quinazoline -4 (3H) ketone:
Such as 1 (6) step of embodiment.
(7) (3- (4 (3H)-quinazolinone)) methyl-1-(4- (2,4- dichloro-benzyloxy) phenyl)-5- (2- thienyl)-
The synthesis of 1,4- pentadiene -3- ketoxime ether:
Such as 1 (7) step of embodiment, difference is with 1- (4- (2,4- dichloro-benzyloxy) phenyl) -5- (2- thienyl) -1,
4- pentadiene -3- ketoxime is raw material.
Embodiment 10
(3- (chloro- 4 (3H)-quinazolinone of 6-)) methyl-1-(4- (3- methylbenzyloxy) phenyl)-5- (2- pyridyl group)-
Synthesis (the compound number I of 1,4- pentadiene -3- ketoxime ether10), comprising the following steps:
(1) synthesis of 4- (hydroxy phenyl)-3- butene-2 -one:
Such as 1 (1) step of embodiment.
(2) synthesis of 1- (4- hydroxy phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketone:
Such as 1 (2) step of embodiment.
(3) synthesis of 1- (4- (3- methylbenzyloxy) phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketone:
Such as 1 (3) step of embodiment, difference is using methyl benzyl chloride as raw material.
(4) synthesis of 1- (4- (3- methylbenzyloxy) phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketoxime:
Such as 1 (4) step of embodiment, difference is with 1- (4- (3- methylbenzyloxy) phenyl) -5- (2- pyridyl group)-Isosorbide-5-Nitrae -
Pentadiene -3- ketone is raw material.
(5) synthesis of 3- (hydroxymethyl) -6- chloro-quinazoline -4 (3H) ketone:
Such as 1 (5) step of embodiment, difference is using (3H) ketone of 6- chloro-quinazoline -4 as raw material.
(6) synthesis of 3- (chloromethyl) quinazoline -4 (3H) ketone:
Such as 1 (6) step of embodiment, difference is using -4 (3H) ketone of 3- (hydroxymethyl) -6- chloro-quinazoline as raw material.
(7) (3- (chloro- 4 (3H)-quinazolinone of 6-)) methyl-1-(4- (3- methylbenzyloxy) phenyl)-5- (2- pyridine
Base) -1,4- pentadiene -3- ketoxime ether synthesis:
Such as 1 (7) step of embodiment, difference is with 1- (4- (3- methylbenzyloxy) phenyl) -5- (2- pyridyl group)-Isosorbide-5-Nitrae -
Pentadiene -3- ketoxime is raw material.
Embodiment 11
(3- (chloro- 4 (3H)-quinazolinone of 6-)) methyl-1-(4- (3- benzyl chloride oxygroup) phenyl)-5- (2- pyridyl group)-1,
Synthesis (the compound number I of 4- pentadiene -3- ketoxime ether11), comprising the following steps:
(1) synthesis of 4- (hydroxy phenyl)-3- butene-2 -one:
Such as 1 (1) step of embodiment.
(2) synthesis of 1- (4- hydroxy phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketone:
Such as 1 (2) step of embodiment.
(3) synthesis of 1- (4- (3- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketone:
Such as 1 (3) step of embodiment.
(4) synthesis of 1- (4- (3- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketoxime:
Such as 1 (4) step of embodiment.
(5) synthesis of 3- (hydroxymethyl) -6- chloro-quinazoline -4 (3H) ketone:
Such as 1 (5) step of embodiment, difference is using (3H) ketone of 6- chloro-quinazoline -4 as raw material.
(6) synthesis of 3- (chloromethyl) -6- chloro-quinazoline -4 (3H) ketone:
Such as 1 (6) step of embodiment, difference is using -4 (3H) ketone of 3- (hydroxymethyl) -6- chloro-quinazoline as raw material.
(7) (3- (chloro- 4 (3H)-quinazolinone of 6-)) methyl-1-(4- (3- benzyl chloride oxygroup) phenyl)-5- (2- pyridyl group)-
The synthesis of 1,4- pentadiene -3- ketoxime ether:
Such as 1 (7) step of embodiment, difference is using -4 (3H) ketone of 3- (chloromethyl) -6- chloro-quinazoline as raw material.
Embodiment 12
(3- (chloro- 4 (3H)-quinazolinone of 6-)) methyl-1-(4- (4- benzyl chloride oxygroup) phenyl)-5- (2- pyridyl group)-1,
Synthesis (the compound number I of 4- pentadiene -3- ketoxime ether12), comprising the following steps:
(1) synthesis of 4- (hydroxy phenyl)-3- butene-2 -one:
Such as 1 (1) step of embodiment.
(2) synthesis of 1- (4- hydroxy phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketone:
Such as 1 (2) step of embodiment.
(3) synthesis of 1- (4- (4- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketone:
Such as 1 (3) step of embodiment, difference be using to benzyl chloride chlorine as raw material.
(4) synthesis of 1- (4- (4- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketoxime:
Such as 1 (4) step of embodiment, difference is with 1- (4- (4- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group)-Isosorbide-5-Nitrae-penta
Diene -3- ketone is raw material.
(5) synthesis of 3- (hydroxymethyl) -6- chloro-quinazoline -4 (3H) ketone:
Such as 1 (5) step of embodiment, difference is using (3H) ketone of 6- chloro-quinazoline -4 as raw material.
(6) synthesis of 3- (chloromethyl) -6- chloro-quinazoline -4 (3H) ketone:
Such as 1 (6) step of embodiment, difference is using -4 (3H) ketone of 3- (hydroxymethyl) -6- chloro-quinazoline as raw material.
(7) (3- (chloro- 4 (3H)-quinazolinone of 6-)) methyl-1-(4- (4- benzyl chloride oxygroup) phenyl)-5- (2- pyridyl group)-
The synthesis of 1,4- pentadiene -3- ketoxime ether:
Such as 1 (7) step of embodiment, difference is with -4 (3H) ketone of 3- (chloromethyl) -6- chloro-quinazoline and 1- (4- (4- chlorine
Benzyloxy) phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketoxime be raw material.
Embodiment 13
(3- (chloro- 4 (3H)-quinazolinone of 6-)) methyl-1-(2- (2- benzyl chloride oxygroup) phenyl)-5- (2- pyridyl group)-1,
Synthesis (the compound number I of 4- pentadiene -3- ketoxime ether13), comprising the following steps:
(1) synthesis of 2- (hydroxy phenyl)-3- butene-2 -one:
Such as 1 (1) step of embodiment, difference is using salicylide as raw material.
(2) synthesis of 1- (2- hydroxy phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketone:
Such as 1 (2) step of embodiment, difference is using 2- (hydroxy phenyl)-3- butene-2 -one as raw material.
(3) synthesis of 1- (2- (2- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketone:
Such as 1 (3) step of embodiment, difference is with o-chloro benzyl chloride and 1- (2- hydroxy phenyl) -5- (2- pyridyl group)-Isosorbide-5-Nitrae -
Pentadiene -3- ketone is raw material.
(4) synthesis of 1- (2- (2- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketoxime:
Such as 1 (4) step of embodiment, difference is with 1- (2- (2- benzyl chloride oxygroup) phenyl) -5- (2- pyridyl group)-Isosorbide-5-Nitrae-penta
Diene -3- ketone is raw material.
(5) synthesis of 3- (hydroxymethyl) -6- chloro-quinazoline -4 (3H) ketone:
Such as 1 (5) step of embodiment, difference is using (3H) ketone of 6- chloro-quinazoline -4 as raw material.
(6) synthesis of 3- (chloromethyl) -6- chloro-quinazoline -4 (3H) ketone:
Such as 1 (6) step of embodiment, difference is using -4 (3H) ketone of 3- (hydroxymethyl) -6- chloro-quinazoline as raw material.
(7) (3- (chloro- 4 (3H)-quinazolinone of 6-)) methyl-1-(2- (2- benzyl chloride oxygroup) phenyl)-5- (2- pyridyl group)-
The synthesis of 1,4- pentadiene -3- ketoxime ether:
Such as 1 (7) step of embodiment, difference is with -4 (3H) ketone of 3- (chloromethyl) -6- chloro-quinazoline and 1- (2- (2- chlorine
Benzyloxy) phenyl) -5- (2- pyridyl group) -1,4- pentadiene -3- ketoxime be raw material.
Embodiment 14
(3- (chloro- 4 (3H)-quinazolinone of 6-)) methyl-1-(4- (2- benzyl chloride oxygroup) phenyl)-5- (3- pyridyl group)-1,
Synthesis (the compound number I of 4- pentadiene -3- ketoxime ether14), comprising the following steps:
(1) synthesis of 4- (hydroxy phenyl)-3- butene-2 -one:
Such as 1 (1) step of embodiment.
(2) synthesis of 1- (4- hydroxy phenyl) -5- (3- pyridyl group) -1,4- pentadiene -3- ketone:
Such as 1 (2) step of embodiment, difference is using 3- pyridine carboxaldehyde as raw material.
(3) synthesis of 1- (4- (2- benzyl chloride oxygroup) phenyl) -5- (3- pyridyl group) -1,4- pentadiene -3- ketone:
Such as 1 (3) step of embodiment, difference is with o-chloro benzyl chloride and 1- (4- hydroxy phenyl) -5- (3- pyridyl group)-Isosorbide-5-Nitrae -
Pentadiene -3- ketone is raw material.
(4) synthesis of 1- (4- (2- benzyl chloride oxygroup) phenyl) -5- (3- pyridyl group) -1,4- pentadiene -3- ketoxime:
Such as 1 (4) step of embodiment, difference is with 1- (4- (2- benzyl chloride oxygroup) phenyl) -5- (3- pyridyl group)-Isosorbide-5-Nitrae-penta
Diene -3- ketone is raw material.
(5) synthesis of 3- (hydroxymethyl) -6- chloro-quinazoline -4 (3H) ketone:
Such as 1 (5) step of embodiment, difference is using (3H) ketone of 6- chloro-quinazoline -4 as raw material.
(6) synthesis of 3- (chloromethyl) -6- chloro-quinazoline -4 (3H) ketone:
Such as 1 (6) step of embodiment, difference is using -4 (3H) ketone of 3- (hydroxymethyl) -6- chloro-quinazoline as raw material.
(7) (3- (chloro- 4 (3H)-quinazolinone of 6-)) methyl-1-(4- (2- benzyl chloride oxygroup) phenyl)-5- (3- pyridyl group)-
The synthesis of 1,4- pentadiene -3- ketoxime ether:
Such as 1 (7) step of embodiment, difference is with -4 (3H) ketone of 3- (chloromethyl) -6- chloro-quinazoline and 1- (4- (2- chlorine
Benzyloxy) phenyl) -5- (3- pyridyl group) -1,4- pentadiene -3- ketoxime be raw material.
The physicochemical property and spectra count of the 1,4- pentadiene -3- ketoxime ether derivative containing 4 (3H)-quinazolinones of synthesis
According to being shown in Table 1, nuclear magnetic resonance spectroscopy (1H NMR) and carbon spectrum (13C NMR) data are shown in Table 2 and table 3.
1 target compound physicochemical property of table and its analytical data of mass spectrum
2 target compound hydrogen nuclear magnetic resonance modal data of table
3 target compound carbon-13 nmr spectra data of table
The activity of resisting tobacco mosaic virus of above-mentioned target compound:
(1) test method
A. Virus purification
Quadratic method (Zhou, X.P. are avenged using week；Xu,Z.X.；Xu,J.；Li,D.B.J.South
Chin.Agric.Univ.1995,16,74-79.), inoculation 3 weeks or more are chosen, TMV systemic infection host Nicotiana
Tabacum.L plant upper blade, is homogenized in phosphate buffer, double gauze filtering, 8000g centrifugation, through 2 polyethylene glycol
Processing, then be centrifuged, precipitating phosphate buffer suspends to get the refining liquid body of TMV is arrived.Entire experiment carries out at 4 DEG C.With purple
The absorbance value of outer spectrophotometric determination 260nm wavelength calculates virus concentration according to formula.
Virus concentration (mg/mL)=(A260× extension rate)/E0.1% 1cm 260nm
Wherein E indicates extinction coefficient, i.e. when wavelength 260nm, concentration is the suspension of 0.1% (1mg/mL), is in light path
Absorbance value when 1cm.The E of TMV0.1% 1cm 260nmIt is 5.0.
B. the living body therapeutic effect that medicament infects TMV
Living body therapeutic effect of the medicament to infecting: the Nicotiana glutinosa of growing way consistent 5-6 leaf phase is selected to pinch, Xiang Quanye sprinkles evenly gold
Emery dips viral juice (6 × 10 with spread pen-3Mg/mL) full leaf virus inoculation is rinsed with clear water after natural drying.To blade
After dry, medicament is gently spread in Zuo Banye with writing brush, the solvent for the concentration that right half leaf spreads corresponding solvent compares, 6-7d postscript
Withered spot number is recorded, inhibiting rate is calculated according to the following formula.
C. the living body protective effect that medicament infects TMV
The living body protective effect that medicament infects TMV: it selects the Nicotiana glutinosa of growing way consistent 5-6 leaf phase to pinch, is existed with writing brush
Zuo Banye gently spreads medicament, and the solvent for the concentration that right half leaf spreads corresponding solvent compares.After for 24 hours, Xiang Quanye sprinkles evenly Buddha's warrior attendant
Sand dips viral juice (6 × 10 with spread pen-3Mg/mL) full leaf virus inoculation is rinsed with clear water, and withered spot number is recorded after 6-7d, is pressed
Following equation calculates inhibiting rate.
Wherein, the average withered spot number for being not coated with application half leaf of agent and the half leaf withered spot number for spreading medicament all use each group to weigh three times
Multiple average.
(2) biological activity test result
Protection and therapeutic activity of 4 target compound of table to tobacco mosaic virus (TMV)
It is control with commodity medicament Ningnanmycin using half leaf withered spot method, when test concentrations are 500 μ g/mL, tests
Treatment and protection activity (be shown in Table 4) of the target compound I1~I14 to tobacco mosaic virus (TMV) (TMV).The test result shows: big
Partial target compound has preferable treatment and protection activity to TMV.Wherein, target compound I2, I4, I5, I6 and I7 couple
TMV possesses preferable therapeutic effect, and inhibiting rate is respectively 53.5%, 55.4%, 55.9%, 59.1% and 53.4%, slightly excellent
In Ningnanmycin (51.8%).Target compound I4、I5And I6Preferable protective effect is possessed to TMV, inhibiting rate is respectively
67.7%, 69.8% and 72.0%, slightly it is better than Ningnanmycin (65.7%).
To further appreciate that the Isosorbide-5-Nitrae-pentadiene -3- ketoxime ether derivative anti-TMV activity for containing 4 (3H)-quinazolinones,
We determine the compound I in terms of therapeutic activity with excellent activity4And I6EC50Value, measurement result are shown in Table 5.
5 compound I of table4、I6With Ningnanmycin to the EC of TMV therapeutic activity50Value
The compound I as the result is shown of table 54And I6To the EC of the therapeutic effect of TMV50Value is 132.9 μ g/mL and 125 μ respectively
G/mL is superior to 207.3 μ g/mL of its comparison medicament Ningnanmycin.This also indicates that such compound possesses preferable inhibition to TMV
Effect, Isosorbide-5-Nitrae-pentadiene -3- ketoxime ether derivative of the part containing 4 (3H)-quinazolinones are presented with plant virus excellent
Good inhibitory activity can be used as potential Antiphytoviral drug, have the prospect preferably applied.
Claims (4)
1. Isosorbide-5-Nitrae-pentadiene -3- ketoxime ether derivative that one kind contains 4 (3H)-quinazolinones, it is characterised in that: its general formula is as follows
It is shown:Wherein, R1For phenyl, substituted-phenyl or optionally replace virtue it is miscellaneous
Ring group；R2For phenyl, substituted-phenyl or the optional aromatic heterocyclic that replaces；R3For on 5,6,7 or 8 of 4 (3H)-quinazolinones
More than one hydrogen atom, methoxyl group, nitro, methyl, trifluoromethyl or the halogen atom contained；The substituted-phenyl is phenyl ring
It is upper o-, m- or p- containing containing on methoxyl group, nitro, methyl, trifluoromethyl or halogen atom or phenyl ring o-, m- and p- two
Methoxyl group, nitro, methyl, trifluoromethyl or halogen atom；The aromatic heterocyclic optionally replaced is furyl, pyridyl group, thiophene
Pheno base, pyrrole radicals, thiazolyl, 2- chloropyridine base or 2- diuril oxazolyl.
2. a kind of system of 1,4- pentadiene -3- ketoxime ether derivative containing 4 (3H)-quinazolinones as described in claim 1
Preparation Method, it is characterised in that: reaction equation is as follows:
3. a kind of 1,4- pentadiene -3- ketoxime ether derivative containing 4 (3H)-quinazolinones according to claim 2
Preparation method, it is characterised in that: describedAnti- synthetic method it is as follows:
(1)
(2)
(3)
(4)
4. a kind of 1,4- pentadiene -3- for containing 4 (3H)-quinazolinones according to claim 2
The preparation method of ketoxime ether derivative, it is characterised in that: describedSynthetic method such as
Under:
(1)
(2)
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| CN103819413A (en) * | 2014-03-19 | 2014-05-28 | 贵州大学 | Pentadienone compound containing quinazolinone aryloxy as well as preparation method and application thereof |
| CN103923061A (en) * | 2014-04-17 | 2014-07-16 | 贵州大学 | Heterocyclic 1,4-pentadiene-3-ketoxime compound as well as preparation method and application thereof |
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| CN103819413A (en) * | 2014-03-19 | 2014-05-28 | 贵州大学 | Pentadienone compound containing quinazolinone aryloxy as well as preparation method and application thereof |
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