CN109336866A - A kind of polysubstituted pyridine cyclics preparation method and application - Google Patents
A kind of polysubstituted pyridine cyclics preparation method and application Download PDFInfo
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Abstract
The invention belongs to the technical fields of pharmaceutical synthesis, and in particular to a kind of with anti-tumor activity, specially a kind of polysubstituted pyridine cyclics preparation method and application.Polysubstituted pyridine cyclics, molecular structure are as follows:, the polysubstituted pyridine cyclics with anti-tumor activity, synthetic method is simple, low in raw material price, structure novel.
Description
Technical field
The invention belongs to the technical fields of pharmaceutical synthesis, and in particular to and it is a kind of with anti-tumor activity, it is specially a kind of
Polysubstituted pyridine cyclics preparation method and application.
Background technique
Nitrogen-containing heterocycle compound is due to having developed many nitrogen-containing heterocycles with extensive bioactivity and by attention
Fungicide, herbicide, insecticide and the medical of class, such compound have become the research hotspot of agrochemicals and medicine,
It has broad application prospects.Such as biochemical reaction is catalyzed in base, enzyme and the coenzyme in ferroheme, chlorophyll, DNA and RNA
Active site and medium-height grass the effective elements of the medicine alkaloid etc., be all nitrogen-containing heterocycle compound；Vitamin few in number, antibiosis
Plain and some phytochromes and vegetable colour all contain jeterocyclic chemistry.The heterocyclic compound synthesized at present is related to medicine, pesticide, dye
Material, biomimetic material, molecular device, energy storage material etc., especially in modern medicines, heterocyclic compound occupy have it is sizable
Specific gravity, it is closely bound up with people's lives.The heterocyclic compound of drug treatment maturation has anti-hypertension systemic drug Kato
Puli, Ramipril, antianginal drug piperazine derivative Trimetazidine, lipid regulating agent Fluvastatin, cyclopyrrolones are calm
Somnifacient zopiclone, Imidazopyridine class somnifacient zolpidem etc..
Pyridine compounds are to be widely used in the conjunction of medicine and pesticide with the active nitrogen-containing heterocycle compound of good biological
At research.Pyridine is mainly used for synthesis medicine, pesticide and rubber chemicals, pyridine farm chemical and is referred to as forth generation pesticide, has height
The feature of effect, low toxicity has good Environmental compatibility with people and biology, meets the demand for development and trend of pesticide, contains pyridine
The compound of ring is increasingly becoming one of Main way of pesticides discovery, has very much development prospect.Such as it is used in pharmaceuticals industry
Anticancer drug Imatinib, the isoniazid etc. of antituberculosis.Promote in Rubber Chemicals Industries for synthesizing the super vulcanization of thiurams
Into agent bis-pentamethylenethiuram tetrasulfide, the super promotor pentamethylene aminodithioformic acid of dithiocarbamates
Piperidinium salt etc..In addition pyridine can also synthesize various new fine-chemical intermediate, and many products belong to small ton newly developed
Position, the medicine of high added value, pesticide and auxiliary agent intermediate, such as 2- picoline, 3- aminomethyl-pyridine, 4- pyridone.
Also for example simultaneously [3,4-d] pyrimidine compound can be used as 5HT2A receptor antagonist to tetrahydropyridine, Atrial Extracellular Signal-Regulated Kinase swashs
Enzyme inhibitor, mammal P2X7 regulator, and there is anti-breast cancer cell MDA-MB-231 proliferation activity and inhibit liver cancer
The proliferation of cell HepG2.
Our companies and Zibo Vocational College have developed a kind of more pyridine cycle compounds with anti-tumor activity cooperatively,
And corresponding bioactivity detection is carried out.
Summary of the invention
The technical problem to be solved by the present invention is to provide a kind of polysubstituted pyridine cyclics preparation method and application,
The polysubstituted pyridine cyclics synthetic method is simple, low in raw material price, and structure novel has anti-tumor activity.
The present invention adopts the following technical scheme that solve above-mentioned technical problem
A kind of polysubstituted pyridine cyclics with anti-tumor activity, which is characterized in that its molecular structure are as follows:
The nuclear-magnetism of the compound, mass spectrum and elemental analysis performance parameter:1H NMR(400MHz,CDCl3): δ 9.37 (d, J=
12.0Hz,1H),8.89-8.81(m,4H),8.53-8.49(m,2H),7.47-7.44(m,4H),7.39-7.31(m,3H),
6.14 (d, J=4.0Hz, 1H), 5.92 (d, J=8.0Hz, 1H), 4.11 (s, 1H), 2.60-2.55 (m, 2H), 2.15 (s,
1H).HR MS(ESI):409.1735[M+H]+.Anal.Calcd for C24H20N6O:C,70.57；H,4.94；N,
20.58.Found:C,70.25；H,4.89；N,20.71.
Another object of the present invention is to provide a kind of systems of polysubstituted pyridine cyclics with anti-tumor activity
Preparation Method, which is characterized in that specific steps are as follows:
(1), 4- pyridone and tert-butyl acetate occur olefination and obtain E-3- (pyrrole under Mn catalyst effect
Pyridine -4- base) tert-butyl acrylate；
(2), E-3- (pyridin-4-yl) tert-butyl acrylate issues raw Michael addition reaction in ammonia atmosphere and obtains R-3-
Amino -3- (pyridin-4-yl)-propanoic acid tert-butyl ester；
(3), R-3- amino -3- (pyridin-4-yl)-propanoic acid tert-butyl ester and the generation amine aldehyde condensation reaction of 4- pyridine carboxaldehyde obtain
R-3- (4- pyridyl-methanamine base) -3- (pyridin-4-yl)-propanoic acid tert-butyl ester；
(4), after R-3- (4- pyridyl-methanamine base) -3- (pyridin-4-yl)-propanoic acid tert-butyl ester hydrolyzes in acid condition again with
Ammonia reacts under copper catalysis to be obtained
(5), urea and 1- (pyridin-3-yl) propyl- 2- alkynes -1- ketone are heated to reflux and (1- are prepared in alcohol solvent
(1- (pyridyl group -3- base) -2- benzal)) urea；
(6), (1- (1- (pyridyl group -3- base) -2- benzal)) urea heats in polyphosphoric acids, and 4- (pyridyl group-is made
3- yl) pyrimidine -2 (H) -one；
(7), 4- (pyridyl group -3- base) pyrimidine -2 (H) -one is in toluene solvant, with POCl3The chloro- 4- of 2- is made in reaction
(pyridin-3-yl) pyridine；
(8)、Substitution reaction occurs with 2- chloro- 4- (pyridin-3-yl) pyridine to obtain
Further preferably, the detailed process of step (1) are as follows: 4- pyridone and second under room temperature and inert gas shielding
Tert-butyl acrylate is added in the tert-butyl alcohol, adds pentacarbonyl manganous bromide and potassium tert-butoxide, is to slowly warm up to 60~90 DEG C of reactions to original
Material disappears；It is cooled to 0~5 DEG C of interior temperature, it is neutral, filtering reacting liquid that glacial acetic acid, which is added dropwise, and adjusts reaction solution pH, after filtrate concentration
To E-3- (pyridin-4-yl) tert-butyl acrylate；As feeding intake for preferred 4- pyridone and tert-butyl acetate and potassium tert-butoxide
Amount molar ratio is 1:1.2:1.
Further preferably, the detailed process of step (2) are as follows: the tertiary fourth of E-3- (pyridin-4-yl) acrylic acid in autoclave
Ester and azanol are added in water and the mixed liquor of n,N-Dimethylformamide, add mercury chloride, in nitrogen displacement autoclave
Gas twice, then be passed through ammonia, so that the pressure in autoclave is reached 0.1~0.3MPa of pressure, be to slowly warm up to 130 DEG C, instead
Should be to raw material fully reacting, filtering reacting liquid, adjusting reaction solution pH with hydrochloric acid solution is 4~5, has a large amount of solids to be precipitated, filters
Reaction solution, filter cake are washed twice through cold methanol, and filter cake is put into THF, then adjusting reaction solution pH with triethylamine is 8~9, and filtering is anti-
Liquid is answered, obtains R-3- amino -3- (pyridin-4-yl)-propanoic acid tert-butyl ester after filtrate concentration；As preferred E-3- (pyridin-4-yl)
The inventory molar ratio of tert-butyl acrylate and azanol is 1:2；The throwing of E-3- (pyridin-4-yl) tert-butyl acrylate and mercury chloride
Doses mass ratio is 5:1.
Further preferably, the detailed process of step (3) are as follows: R-3- amino -3- (pyridin-4-yl)-propanoic acid tert-butyl ester and
4- pyridine carboxaldehyde is added in toluene, adds piperidines, connects reflux condensing tube and water segregator, stirs the mixture for being heated to 100
DEG C, early period needs solvent to remove water, and room temperature, liquid separation, by a small amount of first of lower liquid are down to after then reacting to raw material fully reacting
Benzene extraction repeatedly, merges, concentration of reaction solution obtains R-3- (4- pyridyl-methanamine base) -3- (pyridin-4-yl)-propionic acid with supernatant liquid
The tert-butyl ester.
Further preferably, the detailed process of step (4) are as follows: R-3- (4- pyridyl-methanamine base) -3- (pyridin-4-yl)-the third
Tert-butyl acrylate is added in organic acid, is heated to 60 DEG C of reactions to 2~4h, is then divided exactly organic acid, be transferred to autoclave
In, tetrahydrofuran and stannous chloride is added, is passed through ammonia, pressure in kettle is made to reach 0.1MPa, be heated to flowing back, after reaction
First at reduced pressure conditions, the solvents tetrahydrofurane for boiling off the overwhelming majority, separates pure through silica gel column chromatographyThe organic acid is formic acid or acetic acid；Preferably, R-3- (4- pyridyl-methanamine base) -3- (pyridine -4-
Base) the inventory mass ratio of-propanoic acid tert-butyl ester and stannous chloride is 6.6:1.
Further preferably, the detailed process of step (5) are as follows: urea is dissolved in dehydrated alcohol, heats 50 DEG C, is then slowly dripped
Add 1- (pyridin-3-yl) propyl- 2- alkynes -1- ketone, after dripping off, be heated to gentle reflux, then reacts to there is a large amount of white solid
It is precipitated, TLC detects raw material, and raw material disappears completely, and white solid is filtered, and off-white powder (1- (1- (pyridyl group -3- is dried to obtain
Base) -2- benzal)) urea.
Further preferably, the detailed process of step (6) are as follows: in polyphosphoric acids, (1- (1- (pyridyl group -3- is then added
Base) -2- benzal)) urea is heated to 110 DEG C after being stirred at room temperature 10~30 minutes, after reaction, it is slowly added to water and work
Property charcoal, is filtered after mixing evenly, and filtrate puts refrigerator overnight, is then collected by vacuum filtration the solid of precipitating, with water by solid
It is recrystallized, drying obtains solid 4- (pyridyl group -3- base) pyrimidine -2 (H) -one.
Further preferably, the detailed process of step (7) are as follows: in toluene solvant, it is phonetic that 4- (pyridyl group -3- base) is then added
Pyridine -2 (H) -one, is slowly added dropwise phosphorus oxychloride after being stirred at room temperature 10~30 minutes, is heated to gentle reflux, be stirred to react to original
After material completely disappears, reaction solution is cooled to room temperature, and reaction solution is then poured into quenching reaction in a large amount of ice water, and organic solvent is added
Methylene chloride merges organic phase, is then concentrated after extraction, chromatograph pure 2- chloro- 4- (pyridin-3-yl) pyridine by column.
Further preferably, the detailed process of step (8) are as follows:With 2- chloro- 4- (pyridin-3-yl) pyridine
Substitution reaction occurs in micro passage reaction to obtain
The polysubstituted pyridine cyclics of new method synthesis of the present invention, have anti-tumor activity, and have carried out corresponding
Bioactivity detection.
The present invention also provides application of the polysubstituted pyridine cyclics in preparation treating cancer drug, the cancers
Disease is related to non-small cell lung cancer.
The invention has the benefit that
The compound of the present invention has anti-tumor activity, which can effectively enter the target spot of lung carcinoma cell
In albumen, include completely by target point protein, and active force corresponding with the generation of the amino acid of surrounding, and then is formed with the albumen non-
Normal obvious action effect, is able to suppress the activity of the albumen, to inhibit the growth of tumour cell, has patent medicine potential quality.
Polysubstituted pyridine cyclics with anti-tumor activity of the invention, synthetic method is simple, cost of material is low
It is honest and clean, structure novel.
Detailed description of the invention
Fig. 1 is the drug molecule and tumor targets docking scheme of the embodiment of the present invention 12.
Specific embodiment
Above content of the invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on above content of the present invention belong to this hair
Bright range.
Embodiment 1
In reaction flask, under nitrogen protection, cooling, 20~25 DEG C of interior temperature, 4- pyridone 11g and the tertiary fourth of acetic acid are started
Ester 14g is added drop-wise in tert-butyl alcohol 100mL, and pentacarbonyl manganous bromide 1g and potassium tert-butoxide 11g is added after dripping；Holding is stirred at room temperature
10min is to slowly warm up to 80 DEG C, the reaction was continued 1h, and TLC shows that raw material disappears, and is cooled to 0~5 DEG C of interior temperature, and glacial acetic acid tune is added dropwise
Saving reaction solution pH is neutrality, and filtering reacting liquid obtains E-3- (pyridin-4-yl) tert-butyl acrylate 16g after filtrate concentration；1H
NMR(400MHz,DMSO-d6): δ 8.71 (s, 2H), 7.68-7.64 (m, 2H), 7.37 (d, J=12.0Hz, 1H), 5.29 (d, J
=8.0Hz, 1H), 1.25 (s, 9H)；13C NMR(101MHz,DMSO-d6):165.2,157.9,144.3,141.6,127.4,
123.8,96.5,28.3。
Embodiment 2
In reaction flask, under nitrogen protection, cooling, 20~25 DEG C of interior temperature, 4- pyridone 11g and the tertiary fourth of acetic acid are started
Ester 14g is added drop-wise in tert-butyl alcohol 100mL, and pentacarbonyl manganous bromide 1g and potassium tert-butoxide 11g is added after dripping；Holding is stirred at room temperature
10min is to slowly warm up to 60 DEG C, the reaction was continued 1h, and TLC shows that raw material disappears, and is cooled to 0~5 DEG C of interior temperature, and glacial acetic acid tune is added dropwise
Saving reaction solution pH is neutrality, and filtering reacting liquid obtains E-3- (pyridin-4-yl) tert-butyl acrylate 7g after filtrate concentration；1H
NMR(400MHz,DMSO-d6): δ 8.71 (s, 2H), 7.68-7.64 (m, 2H), 7.37 (d, J=12.0Hz, 1H), 5.29 (d, J
=8.0Hz, 1H), 1.25 (s, 9H)；13C NMR(101MHz,DMSO-d6):165.2,157.9,144.3,141.6,127.4,
123.8,96.5,28.3。
Embodiment 3
In reaction flask, under nitrogen protection, cooling, 20~25 DEG C of interior temperature, 4- pyridone 11g and the tertiary fourth of acetic acid are started
Ester 14g is added drop-wise in tert-butyl alcohol 100mL, and pentacarbonyl manganous bromide 1g and potassium tert-butoxide 11g is added after dripping；Holding is stirred at room temperature
10min is to slowly warm up to 90 DEG C, the reaction was continued 1h, and TLC shows that raw material disappears, and is cooled to 0~5 DEG C of interior temperature, and glacial acetic acid tune is added dropwise
Saving reaction solution pH is neutrality, and filtering reacting liquid obtains E-3- (pyridin-4-yl) tert-butyl acrylate 14g after filtrate concentration；1H
NMR(400MHz,DMSO-d6): δ 8.71 (s, 2H), 7.68-7.64 (m, 2H), 7.37 (d, J=12.0Hz, 1H), 5.29 (d, J
=8.0Hz, 1H), 1.25 (s, 9H)；13C NMR(101MHz,DMSO-d6):165.2,157.9,144.3,141.6,127.4,
123.8,96.5,28.3。
Embodiment 4
E-3- (pyridin-4-yl) tert-butyl acrylate 20g and azanol 6.5g are added to water 100g and N in autoclave,
In the mixed liquor of dinethylformamide 100g, mercury chloride 4g is added, twice with the gas in nitrogen displacement autoclave, then is led to
Entering ammonia, the pressure in autoclave is made to reach 0.2MPa, is to slowly warm up to 130 DEG C, reaction to TLC monitors raw material fully reacting,
Filtering reacting liquid, adjusting reaction solution pH with hydrochloric acid solution is 4~5, has a large amount of solids to be precipitated, filters reaction solution, filter cake is through cold first
Alcohol washes twice, and filter cake is put into THF, then adjusting reaction solution pH with triethylamine is 8~9, filtering reacting liquid, after filtrate concentration
It is 99%, HR MS (ESI): 223.1492 [M+H] to R-3- amino -3- (pyridin-4-yl)-propanoic acid tert-butyl ester 20g, e.e value+。
Embodiment 5
In reaction flask, R-3- amino -3- (pyridin-4-yl)-propanoic acid tert-butyl ester 22g and 4- pyridine carboxaldehyde 12g is added
In toluene 200mL, piperidinyl-1 3g is added, reflux condensing tube and water segregator are connected, stirred the mixture for being heated to 100 DEG C, pass through
Water segregator removes the water generated in reagent includes and reaction, is down to after then proceeding to reaction 1h, TLC monitoring raw material fully reacting
The a small amount of toluene of lower liquid is extracted repeatedly, is merged with supernatant liquid, concentration of reaction solution obtains R-3- (4- pyrrole by room temperature, liquid separation
Pyridine methylamino) -3- (pyridin-4-yl)-propanoic acid tert-butyl ester 25g, e.e value be 99.5%,1H NMR(400MHz,DMSO-d6):δ
8.93-8.86(m,2H),8.71-8.65(m,2H),8.12(t,J1=4.0Hz, J2=12.0Hz, 1H), 7.93 (d, J=
4.0Hz, 1H), 7.32 (d, J=4.0Hz, 2H), 7.07 (s, 1H), 4.15 (d, J=8.0Hz, 1H), 2.93-2.88 (m, 2H)
.1.31(s,9H)。
Embodiment 6
R-3- (4- pyridyl-methanamine base) -3- (pyridin-4-yl)-propanoic acid tert-butyl ester 31g is added to anhydrous formic acid 150mL
In, 60 DEG C of reaction 2h are heated to, then vacuum divides exactly formic acid, and concentrate is transferred in autoclave, and tetrahydrofuran is added
200mL and stannous chloride 5g, being passed through ammonia makes reacting kettle inner pressure reach 0.1MPa, is heated to 60 DEG C, after reaction, filtering
Reaction solution, filtrate separate pure through under reduced pressure, boiling off the solvents tetrahydrofurane of the overwhelming majority through silica gel column chromatography22g,1H NMR(400MHz,DMSO-d6): δ 8.68-8.59 (m, 4H), 7.72 (d, J=8.0Hz, 2H),
7.24 (d, J=4.0Hz, 2H), 6.52 (d, J=12.0Hz, 1H), 4.27 (s, 1H), 2.69-2.65 (m, 2H), 2.25 (s,
1H)；13C NMR(101MHz,DMSO-d6):169.7,153.6,149.1,147.8,129.5,122.2,77.3,71.8,
58.3,46.9。
Embodiment 7
R-3- (4- pyridyl-methanamine base) -3- (pyridin-4-yl)-propanoic acid tert-butyl ester 31g is added to anhydrous acetic acid 150mL
In, 60 DEG C of reaction 2h are heated to, then vacuum divides exactly acetic acid, and concentrate is transferred in autoclave, and tetrahydrofuran is added
200mL and stannous chloride 5g, being passed through ammonia makes reacting kettle inner pressure reach 0.1MPa, is heated to 60 DEG C, after reaction, filtering
Reaction solution, filtrate separate pure through under reduced pressure, boiling off the solvents tetrahydrofurane of the overwhelming majority through silica gel column chromatography17g,1H NMR(400MHz,DMSO-d6): δ 8.68-8.59 (m, 4H), 7.72 (d, J=8.0Hz, 2H),
7.24 (d, J=4.0Hz, 2H), 6.52 (d, J=12.0Hz, 1H), 4.27 (s, 1H), 2.69-2.65 (m, 2H), 2.25 (s,
1H)；13C NMR(101MHz,DMSO-d6):169.7,153.6,149.1,147.8,129.5,122.2,77.3,71.8,
58.3,46.9。
Embodiment 8
In the round-bottomed flask of 1000mL, urea 60g is dissolved in dehydrated alcohol 300mL, heats 50 DEG C, is then slowly dripped
After adding 1- (pyridin-3-yl) propyl- 2- alkynes -1- ketone 160g to drip off, it is heated to gentle reflux, is then reacted 3 hours, is had a large amount of white
Color solid is precipitated, and white solid is filtered, and dries to obtain off-white powder (1- (1- (pyridyl group -3- base) -2- benzal)) urea
160g；1H NMR(400MHz,CDCl3): 9.23 (d, J=8.0Hz, 1H), 8.83 (d, J=24.0Hz, 1H), 8.39 (d, J=
24.0Hz,1H),7.62(t,J1=8.0Hz, J2=8.0Hz, 1H), 6.04 (s, 1H), 1.83 (s, 1H)
Embodiment 9
In the round-bottomed flask of 3000mL, polyphosphoric acids 800g is added, (1- (1- (pyridyl group -3- base) -2- is then added
Benzal)) urea 180g, stirs 20 minutes, is heated to 110 DEG C, stir 1 hour, be slowly added to water 1500mL and active carbon
30g is stirred 1 minute, and filtering, filtrate puts refrigerator overnight, be then collected by vacuum filtration the solid of precipitating, with water by solid into
Row recrystallization, drying obtain solid 4- (pyridyl group -3- base) (H) -one of pyrimidine -2 161g；1H NMR(400MHz,CDCl3):9.16
(s, 1H), 8.79 (d, J=12.0Hz, 1H), 8.42 (d, J=12.0Hz, 1H), 7.67 (t, J1=8.0Hz, J2=8.0Hz,
1H), 7.31 (d, J=24.0Hz, 1H), 4.57 (d, J=16.0Hz, 1H).
Embodiment 10
In the round-bottomed flask of 3000mL, toluene 800mL is added, 4- (pyridyl group -3- base) pyrimidine -2 (H)-is then added
Ketone 170g is stirred at room temperature 10 minutes, and phosphorus oxychloride 300g is slowly added dropwise, and is heated to flowing back, and stirs 2 hours, and it is complete that TLC detects raw material
After totally disappeared mistake, reaction solution is cooled to room temperature, and then reaction solution is poured into ice water 2000mL, and organic solvent dichloromethane is added
700mL, extraction three times, merge organic phase, are then concentrated, obtain the chloro- 4- of pure 2- (pyridin-3-yl) by column chromatography for separation
Pyridine 155g,1H NMR(400MHz,CDCl3): 9.11 (s, 1H), 8.85-8.83 (m, 1H), 8.79 (d, J=4.0Hz, 1H),
8.55-8.54 (m, 1H), 7.92 (d, J=24.0Hz, 2H), 7.43 (d, J=8.0Hz, 1H).
Embodiment 11
2- chloro- 4- (pyridin-3-yl) pyridine 19g is dissolved in n,N-Dimethylformamide 200mL, solution A is configured to；?25g and triethylamine 12g are dissolved in n,N-Dimethylformamide 200mL, are configured to solution B；Solution A and
Solution B is pumped into the silicon carbide reactor device that reaction temperature is 50 DEG C with identical flow velocity 20mL/min by tetrafluoro, and material exists
Substitution reaction occurs in micro passage reaction, and its residence time is 3min, the material after collecting reaction, obtained whole
Reaction solution is poured into water, and is extracted reaction solution 4 times with chloroform 200mL, is merged organic phase, is obtained after concentration35g；1H NMR(400MHz,CDCl3): δ 9.37 (d, J=12.0Hz, 1H), 8.89-
8.81 (m, 4H), 8.53-8.49 (m, 2H), 7.47-7.44 (m, 4H), 7.39-7.31 (m, 3H), 6.14 (d, J=4.0Hz,
1H), 5.92 (d, J=8.0Hz, 1H), 4.11 (s, 1H), 2.60-2.55 (m, 2H), 2.15 (s, 1H) .HR MS (ESI):
409.1735[M+H]+.Anal.Calcd for C24H20N6O:C,70.57；H,4.94；N,20.58.Found:C,70.25；H,
4.89；N,20.71.
Embodiment 12
The method that we use computer drug Computer Aided Design, the target spot egg of resulting compound molecule and tumour cell
White carry out molecular docking, target spot serial number 1M17.We have found that compound can be very good to enter inside target point protein pocket, change
Adduct molecule is surrounded by target point protein residue amino acid, forms very strong function and effect with target spot, wherein compound molecule
Hydrogen bond action can be formed with aspartic acid ASP831, methionine MET769 respectively, it is total to form π-π with phenylalanine PHE699
Yoke effect.It is specifically shown in Fig. 1, is drug molecule and tumor targets docking scheme.
Embodiment 13
Anti-tumor activity test
Growth period lung cell A549 is collected, the anticancer activity of compound is measured with MTS method, by cell with appropriate dense
(every milliliter 5 × 10 of degree4A cell) be added in 96 porocyte culture plates (containing 10% tire calf serum obtain culture solution be made into it is single thin
Born of the same parents' suspension), after culture 24 hours, in 37 DEG C, the CO that volumetric concentration is 5%2Under the conditions of compound effects 72 with various concentration
Hour, then the mixture of MTS (final mass concentration 2mg/mL) and DMS (30 μM of final molar concentration) are directly added into containing thin
In the culture medium of born of the same parents, continue to set incubator incubation 4h.After acting on 4h, liquid is discarded supernatant, DMSO150 μ L is added in every hole, vibrates, carefully
Born of the same parents' survival rate measures absorptivity of the metabolin of MTS effect under enzyme linked immunological monitor 490nm wavelength by it, drug point
SonInhibiting rate IC50 to the cell is 29 μm of olL-1。
Embodiment above describes basic principles and main features of the invention and advantage, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (10)
1. a kind of polysubstituted pyridine cyclics, which is characterized in that its molecular structure are as follows:
2. a kind of preparation method of polysubstituted pyridine cyclics as described in claim 1, which is characterized in that specific steps
Are as follows:
(1), 4- pyridone and tert-butyl acetate occur olefination and obtain E-3- (pyridine -4- under Mn catalyst effect
Base) tert-butyl acrylate；
(2), E-3- (pyridin-4-yl) tert-butyl acrylate issues raw Michael addition reaction in ammonia atmosphere and obtains R-3- ammonia
Base -3- (pyridin-4-yl)-propanoic acid tert-butyl ester；
(3), R-3- amino -3- (pyridin-4-yl)-propanoic acid tert-butyl ester and the generation amine aldehyde condensation reaction of 4- pyridine carboxaldehyde obtain R-3-
(4- pyridyl-methanamine base) -3- (pyridin-4-yl)-propanoic acid tert-butyl ester；
(4), after R-3- (4- pyridyl-methanamine base) -3- (pyridin-4-yl)-propanoic acid tert-butyl ester hydrolyzes in acid condition again with ammonia
It reacts and obtains under copper catalysis
(5), urea and 1- (pyridin-3-yl) propyl- 2- alkynes -1- ketone are heated to reflux and (1- (1- (pyrrole are prepared in alcohol solvent
Piperidinyl -3- base) -2- benzal)) urea；
(6), (1- (1- (pyridyl group -3- base) -2- benzal)) urea heats in polyphosphoric acids, obtains 4- (pyridyl group -3-
Base) pyrimidine -2 (H) -one；
(7), 4- (pyridyl group -3- base) pyrimidine -2 (H) -one is in toluene solvant, with POCl3Reaction, obtains the chloro- 4- (pyridine-of 2-
3- yl) pyridine；
(8)、Substitution reaction occurs with 2- chloro- 4- (pyridin-3-yl) pyridine to obtain
3. the preparation method of polysubstituted pyridine cyclics according to claim 2, which is characterized in that
The detailed process of step (1) are as follows: uncle is added in 4- pyridone and tert-butyl acetate under room temperature and inert gas shielding
In butanol, pentacarbonyl manganous bromide and potassium tert-butoxide are added, 60~90 DEG C of reactions to raw material is to slowly warm up to and disappears；In being cooled to
0~5 DEG C of temperature, it is neutrality that glacial acetic acid, which is added dropwise, and adjusts reaction solution pH, and filtering reacting liquid obtains E-3- (pyridine -4- after filtrate concentration
Base) tert-butyl acrylate；It is 1 as the inventory molar ratio of preferred 4- pyridone and tert-butyl acetate and potassium tert-butoxide:
1.2:1。
4. the preparation method of polysubstituted pyridine cyclics according to claim 2, which is characterized in that
The detailed process of step (2) are as follows: E-3- (pyridin-4-yl) tert-butyl acrylate and azanol are added to water in autoclave
In the mixed liquor of n,N-Dimethylformamide, mercury chloride is added, twice with the gas in nitrogen displacement autoclave, then is passed through
Ammonia makes the pressure in autoclave reach 0.1~0.3MPa of pressure, is to slowly warm up to 130 DEG C, reacts to raw material fully reacting,
Filtering reacting liquid, adjusting reaction solution pH with hydrochloric acid solution is 4~5, has a large amount of solids to be precipitated, filters reaction solution, filter cake is through cold first
Alcohol washes twice, and filter cake is put into THF, then adjusting reaction solution pH with triethylamine is 8~9, filtering reacting liquid, after filtrate concentration
To R-3- amino -3- (pyridin-4-yl)-propanoic acid tert-butyl ester；As preferred E-3- (pyridin-4-yl) tert-butyl acrylate and azanol
Inventory molar ratio be 1:2；The inventory mass ratio of E-3- (pyridin-4-yl) tert-butyl acrylate and mercury chloride is 5:1.
5. the preparation method of polysubstituted pyridine cyclics according to claim 2, which is characterized in that
The detailed process of step (3) are as follows: first is added in R-3- amino -3- (pyridin-4-yl)-propanoic acid tert-butyl ester and 4- pyridine carboxaldehyde
In benzene, piperidines is added, connects reflux condensing tube and water segregator, stirs the mixture for being heated to 100 DEG C, early period needs solvent to remove
Water, is down to room temperature after then reacting to raw material fully reacting, liquid separation extracts a small amount of toluene of lower liquid repeatedly, with upper layer
Liquid merges, and concentration of reaction solution obtains R-3- (4- pyridyl-methanamine base) -3- (pyridin-4-yl)-propanoic acid tert-butyl ester.
6. the preparation method of polysubstituted pyridine cyclics according to claim 2, which is characterized in that
The detailed process of step (4) are as follows: R-3- (4- pyridyl-methanamine base) -3- (pyridin-4-yl)-propanoic acid tert-butyl ester has been added to
In machine acid, be heated to 60 DEG C of reactions to 2~4h, then divide exactly organic acid, be transferred in autoclave, be added tetrahydrofuran and
Stannous chloride is passed through ammonia, and pressure in kettle is made to reach 0.1MPa, is heated to flowing back, and after reaction first at reduced pressure conditions, steams
The solvents tetrahydrofurane for going the overwhelming majority, separates pure through silica gel column chromatographyThe organic acid is
Formic acid or acetic acid；Preferably, R-3- (4- pyridyl-methanamine base) -3- (pyridin-4-yl)-propanoic acid tert-butyl ester and stannous chloride throwing
Doses mass ratio is 6.6:1.
7. the preparation method of polysubstituted pyridine cyclics according to claim 2, which is characterized in that
The detailed process of step (5) are as follows: urea is dissolved in dehydrated alcohol, heats 50 DEG C, 1- (pyridin-3-yl) is then slowly added dropwise
Propyl- 2- alkynes -1- ketone, after dripping off, is heated to gentle reflux, then reacts to there is a large amount of white solid to be precipitated, TLC detection is former
Material, raw material disappear completely, and white solid is filtered, and off-white powder (1- (1- (pyridyl group -3- base) -2- benzal)) is dried to obtain
Urea.
8. the preparation method of polysubstituted pyridine cyclics according to claim 2, which is characterized in that
The detailed process of step (6) are as follows: in polyphosphoric acids, (1- (1- (pyridyl group -3- base) -2- benzal)) urine is then added
Element is heated to 110 DEG C after being stirred at room temperature 10~30 minutes, after reaction, is slowly added to water and active carbon, after mixing evenly
Filtering, filtrate put refrigerator overnight, are then collected by vacuum filtration the solid of precipitating, recrystallized solid with water, dry
Obtain solid 4- (pyridyl group -3- base) pyrimidine -2 (H) -one.
9. the preparation method of polysubstituted pyridine cyclics according to claim 2, which is characterized in that
The detailed process of step (7) are as follows: in toluene solvant, 4- (pyridyl group -3- base) pyrimidine -2 (H) -one is then added, in room
Phosphorus oxychloride is slowly added dropwise after 10~30 minutes in temperature stirring, is heated to being back to after raw material completely disappears, reaction solution is cooled to room
Then reaction solution is poured into quenching reaction in a large amount of ice water by temperature, organic solvent dichloromethane is added, merges organic phase after extraction,
Then it is concentrated, pure 2- chloro- 4- (pyridin-3-yl) pyridine is chromatographed by column.
10. the preparation method of polysubstituted pyridine cyclics according to claim 2, which is characterized in that
The detailed process of step (8) are as follows:With 2- chloro- 4- (pyridin-3-yl) pyridine in micro passage reaction
Substitution reaction occurs to obtain
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