CN105237473B - The 4,5,6 multifunctional amino nicotinic acid nitrile derivatives of dough 2 and preparation method - Google Patents
The 4,5,6 multifunctional amino nicotinic acid nitrile derivatives of dough 2 and preparation method Download PDFInfo
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- CN105237473B CN105237473B CN201510647954.6A CN201510647954A CN105237473B CN 105237473 B CN105237473 B CN 105237473B CN 201510647954 A CN201510647954 A CN 201510647954A CN 105237473 B CN105237473 B CN 105237473B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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- C—CHEMISTRY; METALLURGY
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
A kind of 4,5,6 multifunctional amino nicotinic acid nitrile derivatives of dough 2, by under the conditions of organic solvent and alkali, with 2（1 aryl ethylidene）Malononitrile or 2（1 t butylethylidene）Malononitrile and alkene azide compounds are raw material, are generated after heating response.Provided by the invention 4,5, the 6 multifunctional amino nicotinic acid nitrile derivative synthesizing process of dough 2 are reasonable in design, and raw material is simple and easy to get, easy to operate, and reaction condition is easily achieved, and the reaction time is short, and yield is high, realizes economical and efficient purpose.4 prepared by the present invention, 5, the 6 multifunctional amino cigarette nitrile compounds of dough 2 have certain extracorporeal suppression tumor cell activity, can be used as antitumor lead compound.General structure is as follows：
Description
Technical field
The invention belongs to compound preparation, is related to a kind of preparation method of 4,5,6- multiple functionalized -2- amino nicotinic acid nitrile derivatives,
I.e. with 2- (1- aryl ethylidene) malononitrile or 2- (1- t butylethylidenes) malononitrile in the presence of alkali with alkene nitrine class
Multiple functionalized -2- amino nicotinic acid nitrile the derivatives of 4,5,6- are made in compound reaction.
Background technology
Pyridine loop system is a kind of important nitrogen heterocyclic ring structure in many organic chemistry fileds, and it is alkaloid, biology
Common core texture in active material and clinical medicine.Pyridine derivate generally has the bioactivity of wide spectrum, such as disease-resistant
Substance, antibacterial, anti-inflammatory, treatment angiocardiopathy and anticancer etc..2- amino nicotinic acid nitriles are 2- Amino 3 cyano pyridines, as pyridine
An analog derivative, be equally a kind of important Organic Chemicals, can be wide using its amino and the chemical activity of cyano group
The general synthesis for the intermediate such as medicine, food additives, feed addictive, agricultural chemicals, such as synthesis nicotinic acid, niacinamide, isonicotinic acid,
The derivative of isonicotinic acid hydrazide etc..In recent years, the application field of 2- amino nicotinic acid nitrile and its derivative constantly expands, and it is as a kind of weight
The fine chemicals wanted, there is good market potential and development prospect.
Because having important application value, its synthetic method is constantly subjected to widely pay close attention to 2- amino cigarette nitrile compounds,
And a large amount of useful synthetic methodologies are seen in report.Most of Hantzsch contractings for all employing classics in these methods
Conjunction-dehydrogenation reaction, by chalcone or carbonyls and malononitrile and ammonium acetate the conventional heating 5-6 hours in etoh solvent,
It is condensed and obtains 2- amino cigarette nitrile compounds.This method can also be reacted with solvent-free microwave to be realized, such as Feng Shi (Shi,
F.；Tu,S.；Fang,F.；Li,T.One-potsynthesis of 2-amino-3-cyanopyridine derivatives
Under microwave irradiation withoutsolvent.ARKIVOC 2005, No.i, 137-142.) use four
Component one kettle way is reacted malononitrile, aromatic aldehyde, MIBK and ammonium acetate under microwave radiation, obtains 2- amino nicotinic acid nitrile classes
Compound (formula 1).
In order to improve yield, some researchers are improved such reaction, but primarily directed to catalysts and
In the optimization of solvent, such as：(Tang, the J. such as Tang；Wang,L.；Yao,Y.；Zhang,L.；Wang,W.One-pot
synthesis of2-amino-3-cyanopyridine derivatives catalyzed by ytterbium
perfluorooctanoate[Yb(PFO)3] .Tetrahedron Lett.2011,52,509-511.) utilize Yb (PFO)3For
Catalyst heating reflux reaction 12 hours (formula 2) in ethanol；And (He X, Shang Y, Yu Z, the et such as Xinwei He
al.FeCl3-Catalyzed Four-Component Nucleophilic Addition/Intermolecular
Cyclization Yielding Polysubstituted Pyridine Derivatives.J.Org.Chem.2014,79,
8882-8888) utilize FeCl3For catalyst, polysubstituted cigarette nitrile compounds (formula is made in 6 hours in heating reflux reaction in ethanol
3)。
Formula 1, Feng Shi2- amino nicotinic acid nitrile synthetic methods
Formula 2, Tang2- amino nicotinic acid nitrile synthetic methods
The polysubstituted nicotinic acid nitrile synthetic method of formula 3, Xinwei He
It is although easy to operate for this kind of multicomponent one-pot synthesis of representative above, but multicomponent easily causes more pair
Reaction, makes the yield of target product reduce, and it is more complicated to isolate and purify program, and the reaction time is longer, and some reactions also need to
Expensive catalyst.In addition to multicomponent one pot process 2- amino cigarette nitrile compounds, also other synthetic methods, example
Such as：(Teague, S.J.Synthesis of heavily substituted the 2-aminopyridines by such as Teague
Displacement of a6-methylsulfinyl group.J.Org.Chem.2008,73,9765-9766.) use 2-
(1- aryl ethylidene) malononitrile makees solvent with cyanogen amino carbon disulfide dimethyl phthalate with DMF, under potassium carbonate and piperidines effect
The 2- amino nicotinic acid nitrile (formula 4) of 4- aryl-6s methyl mercapto substitution is synthesized, this method reaction time is longer (it is generally necessary to be stirred at room temperature
Reaction 18 hours), and yield is relatively low (being usually 47%).(Zhang, the D. such as Dengyou Zhang；Sun,H.；Zhang,
L.；Zhou,Y.；Li,C.；Jiang, H.Chem.Commun.2012,48,2909.) in the in the mixed solvent of the tert-butyl alcohol and water,
With Pd (PPh3)4Make catalyst with DBU, directly by different substituted 2- amino -3- bromopyridines and K4[Fe(CN)6]·3H2O reacts
2- amino cigarette nitrile compounds (formula 5) are made, and this method is longer (it is generally necessary to 85 DEG C of stirring reactions there is the reaction time
16 hours), it is necessary to the problems such as being not easy to obtain using the transition-metal catalyst and raw material of costliness.
Formula 4, Teague 2- amino nicotinic acid nitrile synthetic methods
Formula 5, Dengyou Zhang 2- amino nicotinic acid nitrile synthetic methods
The content of the invention
The purpose of purpose of the present invention is that yield is low existing for prior art, the reaction time is long and needs costliness in order to solve
The problems such as catalyst, there is provided the multifunctional dough -2- amino nicotinic acid nitrile derivatives of 4,5,6- of one kind, the general structure of the compound
For：
Wherein：R1For phenyl, 4- bromophenyls, 4- aminomethyl phenyls, 2- thienyls, naphthalene -1- bases, naphthalene -2- bases, the tert-butyl group；R2For
Phenyl, 2- bromophenyls, 3- bromophenyls, 4- bromophenyls, 4- methoxyphenyls；R3For phenyl, 4- chlorphenyls, 4- methoxyphenyls,
Thiophene -2- bases.
It is a further object to provide the preparation side of the multifunctional dough -2- amino nicotinic acid nitrile derivatives of the 4,5,6-
Method, realized by following steps：In organic solvent, with 2- (1- aryl ethylidene) malononitrile or 2- (1- t butylethylidenes)
Malononitrile and alkene azide compounds are raw material, in the presence of alkali, are reacted 3~5 hours in a heated condition, reaction generation
4,5,6- multiple functionalized -2- amino nicotinic acid nitrile derivatives, then through column chromatographic isolation and purification.
The synthetic route of the multifunctional dough -2- amino nicotinic acid nitrile derivatives of 4,5,6-：
Wherein：R1For phenyl, 4- bromophenyls, 4- aminomethyl phenyls, 2- thienyls, naphthalene -1- bases, naphthalene -2- bases, the tert-butyl group；R2For
Phenyl, 2- bromophenyls, 3- bromophenyls, 4- bromophenyls, 4- methoxyphenyls；R3For phenyl, 4- chlorphenyls, 4- methoxyphenyls,
Thiophene -2- bases.
The organic solvent is 1,2- dichloroethanes, dichloromethane or toluene (optimal with 1,2- dichloroethanes)；The alkali
For sodium methoxide or cesium carbonate (optimal with sodium methoxide)；The heating condition is 90~120 DEG C (optimal with 120 DEG C)；Inventory is rubbed
You are at ratio：2- (1- aryl ethylidene) malononitrile：Alkene azide compounds：Sodium methoxide=1:(1~1.2):(0.3~0.8)
(with 1:1:0.5 is optimal), 2- (1- t butylethylidenes) malononitrile：Alkene azide compounds：Sodium methoxide=1:(1~1.2):
(1~2) is (with 1:1:1.5 is optimal).
The specific preparation process of the multifunctional dough -2- amino nicotinic acid nitrile derivatives of 4,5,6- of the present invention is as follows：
(1) by 2- (1- aryl ethylidene) malononitrile (I) or 2- (1- t butylethylidenes) malononitrile, alkene nitrine class
Compound and alkali are added sequentially in seal pipe, using mol ratio as 1:1:0.5 feeds intake, and adds the dissolving of 3~6mL organic solvents, so
3-5 hours are reacted after heating stirring in oil bath；If raw material is 2- (1- t butylethylidenes) malononitrile, rate of charge 1:1:
1.5；
(2) after reaction terminates, by reaction solution dchloromethane, then through washing, saturated common salt washing and anhydrous slufuric acid
Sodium is concentrated under reduced pressure after drying, and finally by silica gel column chromatography separating purification, obtains target product 4,5,6- multifunctional dough -2- ammonia
Base nicotinic acid nitrile derivative (III).
Described 2- (1- aryl ethylidene) malononitrile or the structural formula of 2- (1- t butylethylidenes) malononitrile are：
Wherein R1For phenyl, 4- bromophenyls, 4- aminomethyl phenyls, 2- thienyls, naphthalene -1- bases, naphthalene -2- bases, the tert-butyl group.
The structural formula of described alkene azide compounds is：
Wherein R2For phenyl, 2- bromophenyls, 3- bromophenyls, 4- bromophenyls, 4- methoxyphenyls；R3For phenyl, 4- chlorobenzenes
Base, 4- methoxyphenyls, thiophene -2- bases.
Column chromatography condition used is：Filler is silica gel, and mobile phase is petroleum ether：Ethyl acetate=10~8:1 (volume ratio,
With 9:1 is optimal).
It is also another object of the present invention to provide the 2- amino cigarette nitrile compounds of the multifunctional dough of prepared 4,5,6-
Application in antitumor lead drug is prepared.It the experiment proved that, provided by the invention 4, the 2- amino of 5,6- multifunctional dough
Cigarette nitrile compounds have certain extracorporeal suppression tumor cell activity, can be used as antitumor lead drug.
Multifunctional dough -2- amino nicotinic acid nitrile the derivative synthesizing process of 4,5,6- provided by the invention has the characteristics that：(1)
The 2- amino cigarette nitrile compounds of a series of new are synthesized；(2) this method biological synthesis method is reasonable in design, raw materials used letter
Singly it is easy to get, it is not necessary to easy to operate using metallic catalyst, economical and efficient；(3) reaction condition is easily achieved, and the reaction time is short；
(4) yield is high, and most of product yield is more than 80%.Synthetic method of the present invention overcomes the side of synthesis to a certain extent
Method low yield, the shortcomings that reaction time is long, and synthetic method provided by the invention can synthesize 4,5,6- multifunctional dough
2- amino nicotinic acid nitriles, this synthetic method have no document report.
Embodiment
Below will by specific embodiment, the invention will be further elaborated, but the invention is not restricted to these examples.It is real
Apply raw material 2- (1- aryl ethylidene) malononitrile described in example or 2- (1- t butylethylidenes) malononitrile and alkene nitrine is equal
For prior art, and end-product 4 synthesized in embodiment, 5,6- multifunctional dough -2- amino nicotinic acid nitriles are not prior arts, not
There is document report.
Embodiment 1,2- amino -4- (4- bromophenyls) -5- (2- (4- chlorphenyls) -2- oxoethyls) -6- phenyl nicotinic acid nitriles
By 2- (1- (4- bromophenyls) ethylidene) malononitrile 247.1mg (1mmol), (Z) -2- azidos -1- (4- chlorobenzenes
Base) -3- phenyl propyl- 2- alkene -1- ketone 283.7mg (1mmol) and sodium methoxide 27.0mg (0.5mmol) added in seal pipe, then
1,2- dichloroethanes 5ml are added, after charging, seal pipe is sealed and placed in magnetic agitation in 120 DEG C of oil baths and reacted, is passed through
(solvent is petroleum ether for TLC methods monitoring reaction：Ethyl acetate=3:1 volume ratio), the usual reaction time is 3 hours.
Reaction is cooled to room temperature after terminating, and by reaction solution 60mL dchloromethanes, then washs three with water (3 × 20mL)
Secondary, collected organic layer is simultaneously washed three times, subsequent organic layer anhydrous sodium sulfate drying with saturated aqueous common salt (3 × 20mL), finally
Rotated evaporimeter is concentrated and isolated and purified by column chromatography.The column chromatography condition is specially：Silica gel particle diameter is 200-
300 mesh, wet method dress post, dry method loading, first with mobile phase A (petroleum ether：Ethyl acetate=20:1 volume ratio) 400mL elutions one
It is secondary, then with Mobile phase B (petroleum ether：Ethyl acetate=9:1 volume ratio) persistently elution, monitored by TLC methods and collect target production
Logistics goes out part.Last rotated evaporation under reduced pressure is spin-dried for, and obtains pale yellow powder shape solid product 2- amino -4- (4- bromobenzenes
Base) -5- (2- (4- chlorphenyls) -2- oxoethyls) -6- phenyl nicotinic acid nitrile 407.2mg, yield 81.30%.
The structural formula of the product is：
Faint yellow solid；mp:196.0-197.2℃；1H NMR(500MHz,d6- DMSO) δ 7.65 (d, J=8.2Hz,
2H), 7.58 (d, J=7.9Hz, 2H), 7.44 (d, J=8.1Hz, 2H), 7.33 (s, 5H), 7.21 (d, J=8.0Hz, 2H),
7.08(s,2H),3.98(s,2H)；13C NMR(125MHz,CDCl3)δ197.07,163.49,157.99,155.50,
140.00,139.43,135.16,134.51,132.21,129.80,129.26,129.09,129.00,128.66,127.97,
123.88,117.47,116.12,91.56,40.05.HRMS(ESI):m/z calcd for C26H18BrClN3O[M+H]+:
502.0316,found:502.0313.
It is the control experiment of different condition below：
Comparative example 1-1, with cesium carbonate sodium methoxide is replaced, mole is constant, and remaining is the same as embodiment 1.Obtain pale yellow powder
Shape solid product 2- amino -4- (4- bromophenyls) -5- (2- (4- chlorphenyls) -2- oxoethyls) -6- phenyl nicotinic acid nitrile 353.3mg,
Yield 70.27%.
Comparative example 1-2, with potassium carbonate sodium methoxide is replaced, mole is constant, and remaining is the same as embodiment 1.Obtain pale yellow powder
Shape solid product 2- amino -4- (4- bromophenyls) -5- (2- (4- chlorphenyls) -2- oxoethyls) -6- phenyl nicotinic acid nitrile 149.4mg,
Yield 29.72%.
Comparative example 1-3, with triethylamine sodium methoxide is replaced, mole is constant, and remaining is the same as embodiment 1.Reaction system is miscellaneous, and not
Target product 2- amino -4- (4- bromophenyls) -5- (2- (4- chlorphenyls) -2- oxoethyls) -6- phenyl nicotinic acid nitriles can be generated.
Comparative example 1-4, with piperidines sodium methoxide is replaced, mole is constant, and remaining is the same as embodiment 1.Reaction system is miscellaneous, and can not
Generate target product 2- amino -4- (4- bromophenyls) -5- (2- (4- chlorphenyls) -2- oxoethyls) -6- phenyl nicotinic acid nitriles.
Comparative example 1-5, with sodium hydroxide sodium methoxide is replaced, mole is constant, and remaining is the same as embodiment 1.Obtain yellowish toner
Last shape solid product 2- amino -4- (4- bromophenyls) -5- (2- (4- chlorphenyls) -2- oxoethyls) -6- phenyl nicotinic acid nitriles
149.7mg yield 29.78%.
Comparative example 1-6,1,2- dichloroethanes is replaced with toluene, dosage is constant, and remaining is the same as embodiment 1.Obtain yellowish toner
Last shape solid product 2- amino -4- (4- bromophenyls) -5- (2- (4- chlorphenyls) -2- oxoethyls) -6- phenyl nicotinic acid nitriles
351.5mg yield 69.91%.
Comparative example 1-7,1,2- dichloroethanes is replaced with dichloromethane, dosage is constant, and remaining is the same as embodiment 1.Obtain yellowish
Color powdered solid product 2- amino -4- (4- bromophenyls) -5- (2- (4- chlorphenyls) -2- oxoethyls) -6- phenyl nicotinic acid nitriles
379.8mg yield 75.53%.
Comparative example 1-8,1,2- dichloroethanes is replaced with absolute ethyl alcohol, dosage is constant, and remaining is the same as embodiment 1.Reaction system
It is miscellaneous, and target product 2- amino -4- (4- bromophenyls) -5- (2- (4- chlorphenyls) -2- oxoethyls) -6- phenyl cigarettes can not be generated
Nitrile.
Comparative example 1-9, sodium methoxide is not added, remaining is the same as embodiment 1.Fail to generate target product 2- amino -4- (4- bromobenzenes
Base) -5- (2- (4- chlorphenyls) -2- oxoethyls) -6- phenyl nicotinic acid nitriles.
Comparative example 1-10, sodium methoxide dosage is made into 0.1mmol by 0.5mmol, remaining is the same as embodiment 1.Obtain faint yellow
Pulverulent solids product 2- amino -4- (4- bromophenyls) -5- (2- (4- chlorphenyls) -2- oxoethyls) -6- phenyl nicotinic acid nitriles
134.5mg yield 26.75%.
Comparative example 1-11, sodium methoxide dosage is made into 1mmol by 0.5mmol, remaining is the same as embodiment 1.Obtain yellowish toner
Last shape solid product 2- amino -4- (4- bromophenyls) -5- (2- (4- chlorphenyls) -2- oxoethyls) -6- phenyl nicotinic acid nitriles
178.5mg yield 35.50%.
Comparative example 1-12, sodium methoxide dosage is made into 2mmol by 0.5mmol, remaining is the same as embodiment 1.Obtain yellowish toner
Last shape solid product 2- amino -4- (4- bromophenyls) -5- (2- (4- chlorphenyls) -2- oxoethyls) -6- phenyl nicotinic acid nitriles
183.0mg yield 36.39%.
Comparative example 1-13, reaction temperature is changed to 25 DEG C, remaining is the same as embodiment 1.Fail to generate target product 2- amino -4-
(4- bromophenyls) -5- (2- (4- chlorphenyls) -2- oxoethyls) -6- phenyl nicotinic acid nitriles.
Comparative example 1-14, reaction temperature is changed to 60 DEG C, remaining is the same as embodiment 1.Fail to generate target product 2- amino -4-
(4- bromophenyls) -5- (2- (4- chlorphenyls) -2- oxoethyls) -6- phenyl nicotinic acid nitriles.
Comparative example 1-15, reaction temperature is changed to 90 DEG C, remaining is the same as embodiment 1.Obtain pale yellow powder shape solid product
2- amino -4- (4- bromophenyls) -5- (2- (4- chlorphenyls) -2- oxoethyls) -6- phenyl nicotinic acid nitrile 305.5mg, yield
60.77%.
Double (4- bromophenyls) -5- (2- oxo -2- phenethyls) nicotinic acid nitriles of embodiment 2,2- amino -4,6-
(Z) -2- azido -1- (4- are replaced with (Z) -2- azidos -3- (4- bromophenyls) -1- phenyl propyl- 2- alkene -1- ketone
Chlorphenyl) -3- phenyl propyl- 2- alkene -1- ketone, mole is constant, and remaining is the same as embodiment 1.Obtain pale yellow powder shape solid 2- ammonia
Double (4- bromophenyls) -5- (2- oxo -2- phenethyls) the nicotinic acid nitrile 406.2mg of base -4,6-, yield 74.23%.
Its structural formula is：
Faint yellow solid；mp:168.3-170.1℃；1H NMR(500MHz,d6-DMSO)δ7.66–7.63(m,2H),
7.60-7.54 (m, 5H), 7.39 (t, J=7.8Hz, 2H), 7.32-7.28 (m, 2H), 7.20 (d, J=8.4Hz, 2H), 7.08
(s,2H),3.99(s,2H)；13C NMR(125MHz,CDCl3)δ198.21,162.25,157.94,155.75,138.37,
136.11,135.06,133.67,132.23,131.78,129.87,129.77,128.78,127.86,123.91,123.52,
117.74,115.99,91.95,40.11.HRMS(ESI):m/z calcd for C26H18Br2N3O[M+H]+:547.9791,
found:547.9796。
Embodiment 3,2- amino -5- (2- (4- chlorphenyls) -2- oxoethyls) -4,6- diphenyl nicotinic acid nitriles
2- (1- (4- bromophenyls) ethylidene) malononitrile is replaced with 2- (1- phenyl-ethylenes) malononitrile, mole is constant,
Remaining is the same as embodiment 1.Obtain brown yellow powder solid 2- amino -5- (2- (4- chlorphenyls) -2- oxoethyls) -4,6- hexichol
Base nicotinic acid nitrile 340.7mg, yield 80.38%.
Its structural formula is：
Bright-yellow solid；mp:194.3-195.8℃；1H NMR(500MHz,d6-DMSO)δ7.65–7.62(m,2H),
7.44-7.41 (m, 2H), 7.38 (dd, J=11.4,4.5Hz, 2H), 7.35-7.29 (m, 6H), 7.25-7.21 (m, 2H),
7.00(s,2H),3.96(s,2H).13C NMR(125MHz,CDCl3)δ197.20,163.28,158.03,156.77,
139.69,139.62,136.36,134.80,129.28,129.20,128.98,128.91,128.86,128.60,128.08,
128.06,117.66,116.25,91.92,40.10.HRMS(ESI):m/z calcd for C26H19ClN3O[M+H]+:
424.1211,found:424.1219。
Embodiment 4,2- amino -6- (2- bromophenyls) -5- (2- oxo -2- phenethyls) -4- phenyl nicotinic acid nitriles
2- (1- (4- bromophenyls) ethylidene) malononitrile is replaced with 2- (1- phenyl-ethylenes) malononitrile, with (Z) -2- nitrine
Base -3- (2- bromophenyls) -1- phenyl propyl- 2- alkene -1- ketone replaces (Z) -2- azidos -1- (4- chlorphenyls) -3- phenyl propyl-s 2-
Alkene -1- ketone, mole is constant, and remaining is the same as embodiment 1.Obtain yellow powdery solid 2- amino -6- (2- bromophenyls) -5- (2-
Oxo -2- phenethyls) -4- phenyl nicotinic acid nitrile 365.4mg, yield 78.03%.
Its structural formula is：
Yellow solid；mp:203.7-204.8℃；1H NMR(500MHz,d6-DMSO)1H NMR(500MHz,DMSO)δ
7.63 (d, J=7.9Hz, 1H), 7.55 (d, J=7.6Hz, 2H), 7.49 (dd, J=14.2,7.2Hz, 2H), 7.38 (d, J=
7.9Hz, 2H), 7.36-7.26 (m, 4H), 7.22 (dd, J=7.7,1.2Hz, 1H), 7.19-7.13 (m, 2H), 7.08 (s,
2H), 3.86 (d, J=18.3Hz, 1H), 3.70 (d, J=18.3Hz, 1H)13C NMR(125MHz,CDCl3)δ197.59,
162.18,158.13,156.59,140.07,136.53,136.10,133.18,132.73,130.60,130.24,129.37,
128.98,128.87,128.50,128.29,128.14,127.72,121.29,118.85,116.24,92.34,
39.33.HRMS(ESI):m/z calcd for C26H19BrN3O[M+H]+:468.0706,found:468.0714。
Embodiment 5,2- amino -4- (4- bromophenyls) -5- (2- oxos -2- (thiophene -2- bases) ethyl) -6- phenyl nicotinic acid nitriles
(Z) -2- azido -1- (4- are replaced with (Z) -2- azido -3- phenyl -1- (thiophene -2- bases) propyl- 2- alkene -1- ketone
Chlorphenyl) -3- phenyl propyl- 2- alkene -1- ketone, mole is constant, and remaining is the same as embodiment 1.Obtain brown powder solid 2- amino-
4- (4- bromophenyls) -5- (2- oxos -2- (thiophene -2- bases) ethyl) -6- phenyl nicotinic acid nitrile 401.1mg, yield 84.55%.
Its structural formula is：
Brown solid；mp:215.4-216.2℃；1H NMR(500MHz,d6- DMSO) δ 7.90 (d, J=4.4Hz, 1H),
7.59 (d, J=8.1Hz, 2H), 7.54 (d, J=2.9Hz, 1H), 7.36 (s, 5H), 7.23 (d, J=8.0Hz, 2H), 7.04
(m,3H),3.93(s,2H).13C NMR(125MHz,CDCl3)δ190.69,163.64,157.95,155.60,143.01,
139.46,135.19,134.09,132.18,131.95,129.96,129.05,128.63,128.18,128.12,123.83,
117.54,116.11,91.57,40.54.HRMS(ESI):m/z calcd for C24H17BrN3OS[M+H]+:474.0270,
found:474.0276。
Embodiment 6,2- amino -5- (2- (4- methoxyphenyls) -2- oxoethyls) -4,6- diphenyl nicotinic acid nitriles
2- (1- (4- bromophenyls) ethylidene) malononitrile is replaced with 2- (1- phenyl-ethylenes) malononitrile, to be folded with (Z) -2-
Nitrogen base -1- (4- methoxyphenyls) -3- phenyl propyl- 2- alkene -1- ketone replaces (Z) -2- azidos -1- (4- chlorphenyls) -3- phenyl
Propyl- 2- alkene -1- ketone, mole is constant, and remaining is the same as embodiment 1.Obtain crocus pulverulent solids 2- amino -5- (2- (4- methoxies
Base phenyl) -2- oxoethyls) -4,6- diphenyl nicotinic acid nitrile 338.0mg, yield 80.57%.
Its structural formula is：
Orange solid；mp:188.8-189.5℃；1H NMR(500MHz,d6- DMSO) δ 7.63 (d, J=8.8Hz,
2H), 7.40-7.34 (m, 3H), 7.33 (s, 5H), 7.23 (d, J=6.8Hz, 2H), 6.95 (s, 2H), 6.86 (d, J=
8.8Hz,2H),3.90(s,2H),3.76(s,3H).13C NMR(125MHz,CDCl3)δ196.74,163.58,163.28,
157.90,156.78,139.78,136.48,130.13,129.54,129.16,128.85,128.81,128.52,128.16,
128.13,118.27,116.39,113.67,91.90,55.54,39.80.HRMS(ESI):m/z calcd for
C27H22N3O2[M+H]+:420.1707,found:420.1705。
Embodiment 7,2- amino -5- (2- (4- chlorphenyls) -2- oxoethyls) -6- phenyl -4- (thiophene -2- bases) nicotinic acid nitrile
2- (1- (4- bromophenyls) ethylidene) malononitrile is replaced with 2- (1- (thiophene -2- bases) ethylidene) malononitrile, mole
Measure constant, remaining is the same as embodiment 1.Obtain brown powder solid 2- amino -5- (2- (4- chlorphenyls) -2- oxoethyls) -6-
Phenyl -4- (thiophene -2- bases) nicotinic acid nitrile 351.7mg, yield 81.82%.
Its structural formula is：
Brown solid；mp:202.7-204.1℃；1H NMR(500MHz,d6- DMSO) δ 7.75 (d, J=8.6Hz, 2H),
7.66 (dd, J=5.0,1.1Hz, 1H), 7.48 (d, J=8.6Hz, 2H), 7.35-7.32 (m, 5H), 7.11 (dd, J=3.5,
1.1Hz,1H),7.08–7.04(m,3H),4.06(s,2H).13C NMR(125MHz,CDCl3)δ197.12,163.42,
158.12,149.61,139.87,139.54,135.39,134.72,129.46,129.40,129.10,128.99,128.65,
128.16,128.04,127.65,118.92,116.18,92.81,40.59.HRMS(ESI):m/z calcd for
C24H17ClN3OS[M+H]+:430.0775,found:430.0779。
Embodiment 8,2- amino -6- (4- methoxyphenyls) -5- (2- oxo -2- phenethyls) -4- phenyl nicotinic acid nitriles
2- (1- (4- bromophenyls) ethylidene) malononitrile is replaced with 2- (1- phenyl-ethylenes) malononitrile, with (Z) -2- nitrine
Base -3- (4- methoxyphenyls) -1- phenyl propyl- 2- alkene -1- ketone replaces (Z) -2- azidos -1- (4- chlorphenyls) -3- phenyl propyl-s
2- alkene -1- ketone, mole is constant, and remaining is the same as embodiment 1.Obtain pale yellow powder shape solid 2- amino -6- (4- methoxybenzenes
Base) -5- (2- oxo -2- phenethyls) -4- phenyl nicotinic acid nitrile 341.7mg, yield 81.47%.
Its structural formula is：
Faint yellow solid；mp:179.3-181.7℃；1H NMR(500MHz,d6- DMSO) δ 7.64 (d, J=7.6Hz,
2H), 7.53 (t, J=7.4Hz, 1H), 7.37 (t, J=8.4Hz, 4H), 7.32 (d, J=8.5Hz, 3H), 7.22 (d, J=
7.1Hz, 2H), 6.92 (s, 2H), 6.90 (d, J=8.7Hz, 2H), 4.01 (s, 2H), 3.71 (s, 3H)13C NMR(125MHz,
CDCl3)δ198.64,163.06,160.16,157.94,156.75,136.63,136.58,133.19,132.19,129.70,
129.15,128.85,128.55,128.09,127.83,117.97,116.46,113.98,91.55,77.41,77.16,
76.91,55.44,40.49.HRMS(ESI):m/z calcd for C27H22N3O2[M+H]+:420.1707,found:
420.1716。
Embodiment 9,2- amino -6- (3- bromophenyls) -5- (2- oxo -2- phenethyls) -4- phenyl nicotinic acid nitriles
2- (1- (4- bromophenyls) ethylidene) malononitrile is replaced with 2- (1- phenyl-ethylenes) malononitrile, with (Z) -2- nitrine
Base -3- (3- bromophenyls) -1- phenyl propyl- 2- alkene -1- ketone replaces (Z) -2- azidos -1- (4- chlorphenyls) -3- phenyl propyl-s 2-
Alkene -1- ketone, mole is constant, and remaining is the same as embodiment 1.Obtain yellow powdery solid 2- amino -6- (3- bromophenyls) -5- (2-
Oxo -2- phenethyls) -4- phenyl nicotinic acid nitrile 384.0mg, yield 82%.
Its structural formula is：
Yellow solid；mp:154.5-156.7℃；1H NMR(500MHz,d6- DMSO) δ 7.63 (d, J=7.5Hz, 2H),
7.56-7.51 (m, 3H), 7.41-7.34 (m, 6H), 7.30 (t, J=7.7Hz, 1H), 7.24 (d, J=6.9Hz, 2H), 7.04
(s,2H),3.98(s,2H).13C NMR(125MHz,CDCl3)δ198.33,161.59,157.91,157.04,141.67,
136.48,136.21,133.34,131.97,131.38,130.07,129.34,128.94,128.61,128.05,127.82,
126.73,122.72,118.08,116.13,92.37,40.10.HRMS(ESI):m/z calcd for C26H19BrN3O[M+
H]+:468.0706,found:468.0710。
Embodiment 10,2- amino -5- (2- (4- chlorphenyls) -2- oxoethyls) 6- phenyl) -4- (p-methylphenyl) nicotinic acid nitrile
2- (1- (4- bromophenyls) ethylidene) malononitrile, mole are replaced with 2- (1- (p-methylphenyl) ethylidene) malononitrile
Constant, remaining is the same as embodiment 1.Obtain pale yellow powder shape solid 2- amino -5- (2- (4- chlorphenyls) -2- oxoethyls) 6- benzene
Base) -4- (p-methylphenyl) nicotinic acid nitrile 353.1mg, yield 80.63%.
Its structural formula is：
Faint yellow solid；mp:201.2-203.5℃；1H NMR(500MHz,d6- DMSO) δ 7.63 (d, J=8.7Hz,
2H), 7.43 (d, J=8.7Hz, 2H), 7.35-7.31 (m, 5H), 7.17 (d, J=7.8Hz, 2H), 7.11 (d, J=8.1Hz,
2H),6.94(s,2H),3.96(s,2H),2.24(s,3H).13C NMR(125MHz,CDCl3)δ197.30,163.23,
158.00,156.93,139.77,139.64,139.24,134.87,133.40,129.60,129.27,128.92,128.82,
128.60,128.07,127.98,117.87,116.44,92.04,40.12,21.39.HRMS(ESI):m/z calcd for
C27H21ClN3O[M+H]+:438.1368,found:438.1369。
Embodiment 11,2- amino -4- (naphthalene -2- bases) -5- (2- oxo -2- phenylethyls) -6- phenyl nicotinic acid nitriles
2- (1- (4- bromophenyls) ethylidene) malononitrile is replaced with 2- (1- (naphthalene -2- bases) ethylidene) malononitrile, with (Z) -
2- azido -1,3- diphenylprop -2- alkene -1- ketone replaces (Z) -2- azidos -1- (4- chlorphenyls) -3- phenyl propyl- 2- alkene -1-
Ketone, mole is constant, and remaining is the same as embodiment 1.Obtain brown yellow powder solid 2- amino -4- (naphthalene -2- bases) -5- (2- oxos -
2- phenylethyls) -6- phenyl nicotinic acid nitrile 350.2mg, yield 79.67%.
Its structural formula is：
Bright-yellow solid；mp:200.1-202.2℃；1H NMR(500MHz,d6- DMSO) δ 7.92 (d, J=8.5Hz,
1H), 7.90-7.87 (m, 2H), 7.83 (s, 1H), 7.58-7.55 (m, 2H), 7.54-7.50 (m, 2H), 7.43 (t, J=
7.4Hz, 1H), 7.39-7.36 (m, 3H), 7.34 (dd, J=7.5,5.0Hz, 3H), 7.25 (t, J=7.8Hz, 2H), 7.01
(s,2H),4.02(s,2H).13C NMR(125MHz,CDCl3)δ198.50,163.39,158.02,156.71,139.77,
136.51,133.85,133.30,133.11,133.02,128.92,128.84,128.59,128.44,128.14,127.89,
127.87,127.72,127.01,126.79,125.44,118.27,116.40,92.06,40.28.HRMS(ESI):m/z
calcd for C30H22N3O[M+H]+:440.1757,found:440.1764。
Embodiment 12,2- amino -4- (naphthalene -1- bases) -5- (2- oxo -2- phenylethyls) -6- phenyl nicotinic acid nitriles
2- (1- (4- bromophenyls) ethylidene) malononitrile is replaced with 2- (1- (naphthalene -1- bases) ethylidene) malononitrile, with (Z) -
2- azido -1,3- diphenylprop -2- alkene -1- ketone replaces (Z) -2- azidos -1- (4- chlorphenyls) -3- phenyl propyl- 2- alkene -1-
Ketone, mole is constant, and remaining is the same as embodiment 1.Obtain yellow powdery solid 2- amino -4- (naphthalene -1- bases) -5- (2- oxos -2-
Phenylethyl) -6- phenyl nicotinic acid nitrile 344.5mg, yield 78.39%.
Its structural formula is：
Yellow solid；mp:210.1-212.0℃；1H NMR(500MHz,d6- DMSO) δ 7.94 (dd, J=5.5,3.9Hz,
1H), 7.88 (d, J=8.3Hz, 1H), 7.54 (dt, J=6.3,2.8Hz, 2H), 7.48-7.41 (m, 5H), 7.38-7.33 (m,
5H), 7.31 (dd, J=7.1,0.9Hz, 1H), 7.22 (t, J=7.8Hz, 2H), 7.03 (s, 2H), 3.97 (d, J=18.3Hz,
1H), 3.64 (d, J=18.3Hz, 1H)13C NMR(125MHz,CDCl3)δ198.07,163.44,158.05,155.42,
139.67,136.50,133.60,133.42,132.97,130.27,129.62,128.98,128.77,128.59,128.32,
127.56,127.25,127.23,126.50,125.42,124.62,119.45,116.01,92.85,39.78.HRMS
(ESI):m/z calcd for C30H22N3O[M+H]+:440.1757,found:440.1759。
Embodiment 13, the 2- amino -4- tert-butyl groups -5- (2- oxo -2- phenylethyls) -6- phenyl nicotinic acid nitriles
2- (1- (4- bromophenyls) ethylidene) malononitrile is replaced with 2- (1- t butylethylidenes) malononitrile, folded with (Z) -2-
Nitrogen base -1,3- diphenylprop -2- alkene -1- ketone replaces (Z) -2- azidos -1- (4- chlorphenyls) -3- phenyl propyl- 2- alkene -1- ketone,
Mole is constant, and sodium methoxide dosage is changed to 1.5mmol, and remaining is the same as embodiment 1.Obtain pale yellow powder shape solid 2- amino -4-
The tert-butyl group -5- (2- oxo -2- phenylethyls) -6- phenyl nicotinic acid nitrile 316.0mg, yield 85.52%.
Its structural formula is：
Faint yellow solid；mp:218.2-219.1℃；1H NMR(500MHz,d6-DMSO)δ7.83–7.80(m,2H),
7.61-7.57 (m, 1H), 7.45 (t, J=7.8Hz, 2H), 7.30-7.24 (m, 3H), 7.15 (dd, J=7.8,1.6Hz, 2H),
6.63(s,2H),4.53(s,2H),1.50(s,9H).13C NMR(125MHz,CDCl3)δ198.45,165.46,163.35,
159.83,141.10,136.57,133.33,128.74,128.58,128.41,127.87,127.71,119.49,117.21,
90.42,42.32,39.25,32.33.HRMS(ESI):m/z calcd for C24H24N3O[M+H]+:370.1914,found:
370.1913。
Embodiment 14, antitumor activity experiment
With people's epidermis cancer cell (A431) for test cell strain, obtained compound is carried out using mtt assay external anti-swollen
Oncocyte activity rating.Specific implementation method is as follows：
(1) the A431 cells of exponential phase are collected, and its kind is entered in 96 orifice plates, it is 3000/hole to make cell density
(being 200 μ L per hole culture medium)；
(2) testing compound is dissolved in DMSO, it is 20mmol/L to make its concentration, then draws 1 μ L respectively and is added to
In 96 orifice plates, now final concentration of 100 μm of ol/L of compound.At 37 DEG C, 5%CO2Under the conditions of be incubated altogether with A431 cell lines
48 hours.
(3) 20 μ L 5mg/mL MTT solution is added into every hole, continues to cultivate 4 hours；
(4) supernatant in 96 orifice plates is sucked, then to the DMSO that 150 μ L are added in every hole, mixes 5 minutes, then
Its absorbance (OD values) is detected under ELIASA 570nm wavelength.Finally calculate inhibiting rate (being shown in Table 1), the calculating of inhibiting rate
Formula is：Cell inhibitory rate=[1- (dosing group OD/ control group OD)] × 100%
The result tested from antitumor activity, the 2- amino nicotinic acid nitrile class chemical combination of prepared 4,5,6- multifunctional dough
Thing has certain extracorporeal suppression tumor cell activity, can be used as antitumor lead compound.
Inhibiting rate of the 1 100 μm of ol/L compounds of table to A431 tumour cells
| Compound | Inhibiting rate | Compound | Inhibiting rate |
| Embodiment 1 | 79% | Embodiment 7 | 70% |
| Embodiment 2 | 62% | Embodiment 8 | 23% |
| Embodiment 3 | 63% | Embodiment 9 | 69% |
| Embodiment 4 | 80% | Embodiment 10 | 61% |
| Embodiment 5 | 50% | Embodiment 11 | 49% |
| Embodiment 6 | 60% | Embodiment 12 | 70% |
Finally, it is also necessary to it is noted that listed above is only several specific embodiments of the invention.Obviously, this hair
It is bright to be not limited to above example, there can also be many deformations.One of ordinary skill in the art can be from present disclosure
All deformations for directly exporting or associating, are considered as protection scope of the present invention.
Claims (4)
1. one kind 4,5, the multifunctional dough -2- amino nicotinic acid nitrile derivatives of 6-, it is characterised in that the general structure of the compound
For：
Wherein：R1For phenyl, 4- bromophenyls, 4- aminomethyl phenyls, 2- thienyls, naphthalene -1- bases, naphthalene -2- bases, the tert-butyl group；R2For benzene
Base, 2- bromophenyls, 3- bromophenyls, 4- bromophenyls, 4- methoxyphenyls；R3For phenyl, 4- chlorphenyls, 4- methoxyphenyls, thiophene
Fen -2- bases.
2. the preparation method of 4 described in claim 1,5,6- multifunctional dough -2- amino nicotinic acid nitrile derivatives, it is characterised in that
Realized by following steps：In organic solvent is 1,2- dichloroethanes, with 2-（1- aryl ethylidene）Malononitrile or 2-（Uncle 1-
Butyl ethylidene）Malononitrile and alkene azide compounds are raw material, in the presence of alkali is sodium methoxide, in 120 DEG C of fire-bars
Reacted under part 3-5 hours, reaction 4,5,6- multifunctional dough -2- amino nicotinic acid nitrile derivatives of generation, then through column chromatographic isolation and purification；
Synthetic route is as follows：
Wherein：R1For phenyl, 4- bromophenyls, 4- aminomethyl phenyls, 2- thienyls, naphthalene -1- bases, naphthalene -2- bases, the tert-butyl group；R2For benzene
Base, 2- bromophenyls, 3- bromophenyls, 4- bromophenyls, 4- methoxyphenyls；R3For phenyl, 4- chlorphenyls, 4- methoxyphenyls, thiophene
Fen -2- bases.
3. the preparation method of according to claim 24,5,6- multifunctional dough -2- amino nicotinic acid nitrile derivatives, its feature exist
In specific preparation process is as follows：
（1）By 2-（1- aryl ethylidene）Malononitrile or 2-（1- t butylethylidenes）Malononitrile, alkene azide compounds and
Sodium methoxide is added sequentially in seal pipe, if raw material is 2-（1- aryl ethylidene）During malononitrile, using mol ratio as 1: (1~
1.2):(0.3 ~ 0.8) feeds intake, if raw material is 2-（1- t butylethylidenes）During malononitrile, molar ratio 1: (1~
1.2):(1 ~ 2), and add 3 ~ 6 mL 1,2- dichloroethanes dissolving, the heating response 3-5 hours in 120 DEG C of oil baths；
（2）After reaction terminates, done by reaction solution dchloromethane, then through washing, saturated common salt washing and anhydrous sodium sulfate
It is concentrated under reduced pressure after dry, finally by column chromatographic isolation and purification, obtains target product 4,5,6- multifunctional dough -2- amino nicotinic acid nitriles spread out
Biology.
4. 4 according to Claims 2 or 3,5,6- multifunctional dough -2- amino nicotinic acid nitrile derivative preparation methods, its feature
It is, column chromatography condition is used in preparation：Filler is silica gel, and mobile phase is petroleum ether：Ethyl acetate=10 ~ 8:1.
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