CN105732497A - 2-aryl-4-methyl pyridine-1 (2H)-ketone derivative and synthesis method and application thereof - Google Patents
2-aryl-4-methyl pyridine-1 (2H)-ketone derivative and synthesis method and application thereof Download PDFInfo
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- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
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Abstract
The invention provides a 2-aryl-4-methyl pyridine-1 (2H)-ketone derivative as shown in the formula (II).The synthesis method includes the steps that under the protection of N2, a compound shown in the formula (I) serves as the raw materials, in organic solvent, under existence of alkaline matter, a Pd catalyst, a phosphorus ligand and auxiliaries, a reaction is conducted for 6-24 hours at the temperature of 60-120 DEG C, then reaction liquid is subjected to postprocessing, and a product as shown in the formula (II) is obtained; the synthesis operation of the compound is simple and easy to implement, raw materials are cheap and easy to obtain, the reaction condition is mild, reaction time is short, and good compatibility among various substituent groups is achieved ; the compound has better anti-fibrosis biological activity compared with pirfenidone, and a basis is laid for development of novel and efficient anti-fibrosis drugs.
Description
(1) technical field
The present invention relates to a kind of new there is fibrosis bioactive compound 2-aryl-4-methyl ring pyridine
-1 (2H)-one analog derivative and synthetic method thereof and application.
(2) background technology
Fibrotic disease refers to that the tissue substantial cellular that the factor such as inflammation, damage causes epimatrix downright bad, tissue inner cell is different
Normal increases and the process of excessive deposition initiation pathology.Fibrosis is likely to occur in all of organ of human body and tissue, such as lung
Fibrosis, renal fibrosis, hepatic fibrosis, myocardial fibrosis etc..Fibrosis can aggravate one's illness deterioration, causes organ functional
Obstacle, thus results in organ failure the most dead.Therefore, fibrotic disease is a class serious harm human life and healthy
Important diseases.
Pirfenidone (Pirfenidone), is a kind of fibrosis new drug, provides new Therapeutic Method for fibrotic disease.
Pirfenidone is the micromolecular compound that 20 century 70s find, its chemical name is 5-methyl isophthalic acid-phenylpyridine-2 (1H)
Ketone.It has wide spectrum anti-fibrosis effect, the little molecule anti-fibrosis medicine of first listing.In December, 2008, the non-Buddhist nun of pyrrole
Ketone tablet (trade name Pirespa) first lists in Japan.In March, 2011, EU Committee have approved pirfenidone tablets
(trade name Pirfenex) is used for treating the mild to moderate idiopathic pulmonary fibrosis of adult.In the U.S., pirfenidone is the most
Complete the III clinical trial phase of pulmonary fibrosis, and the II clinical trial phase of renal fibrosis and multiple sclerosis, and
On October 15th, 2014 is as treatment pulmonary fibrosis medicine listing.The structural formula of pirfenidone is as follows:
Research shows, pirfenidone has the first mistake that some shortcomings, such as action effect are more weak, stronger in process of clinical application
The features such as effect and internal metabolism are fast.So, it still cannot function as preferable anti-fibrosis medicine.
Research to anti-fibrosis medicine at present is mainly both direction: one, the modification of pirfenidone skeleton;Its two, completely newly
Design synthesis class pirfenidone compounds.Such as: 2011, Hu Gaoyun etc. design targetedly and have synthesized N-replacement
The derivant of phenyl hydrogenated quinoline ketone parent nucleus has also carried out screening active ingredients to the target compound of synthesis.Result of study shows, such
The derivant of quinolinone parent nucleus has suppression NIH3T3The activity of cell proliferation.
And brand-new design synthesizes 2-aryl-4-methyl ring pyridine-1 (2H)-one analog derivative and it is carried out fibrosis biology
Activity research was not the most reported.
(3) summary of the invention
It is an object of the invention to provide and a kind of new there is fibrosis bioactive compound 2-aryl-4-methyl ring also
Pyridine-1 (2H)-one analog derivative and synthetic method thereof and application.Brand-new design of the present invention has synthesized 2-aryl-4-methyl ring pyrrole
Pyridine-1 (2H)-one analog derivative, i.e. with the Carbox amide containing Br and pi-allyl as raw material, by intramolecular Heck
Reaction finally gives target product.The compounds of this invention has fibrosis biological activity more more preferable than pirfenidone.
For achieving the above object, the present invention adopts the following technical scheme that
2-aryl-4-methyl ring shown in a kind of formula (II) pyridine-1 (2H)-one analog derivative:
In formula (II):
R is hydrogen, methyl, chlorine, bromine or fluorine;
N is 1,2,3 or 4.
Further, described 2-aryl-4-methyl ring pyridine-1 (2H)-one analog derivative are chemical combination shown in formula (2a)~(2r)
One of thing:
Present invention also offers a kind of described 2-aryl-4-methyl ring the synthetic method of pyridine-1 (2H)-one analog derivative, described
Synthetic method be:
N2Under protective condition, it is former with the compound (containing Br and the Carbox amide of pi-allyl) shown in formula (I)
Material, in organic solvent, in the presence of alkaline matter, Pd catalyst, phosphorus part, auxiliary agent, reacts 6~24h in 60~120 DEG C,
Reactant liquor is post-treated afterwards, obtains product shown in formula (II) (2-aryl-4-methyl ring pyridine-1 (2H)-one analog derivative).
In formula (I) or formula (II), R, n are as defined above.
In synthetic method of the present invention:
Described organic solvent is toluene, acetonitrile, THF, ethyl acetate, DMSO, DMF or DMAc;Recommend described
The volumetric usage of organic solvent is calculated as 2~5mL/mmol with the amount of the material of compound shown in formula (I).
Described alkaline matter is triethylamine, potassium acetate, potassium carbonate, sodium carbonate, Disilver carbonate, cesium carbonate or potassium tert-butoxide.
Described Pd catalyst is Pd (OAc)2、PdCl2(PPh3)2、PdCl2、Pd(PPh3)4Or chlorination Allylpalladium dimer.
Described phosphorus part is tributylphosphine, triphenylphosphine (PPh3), adjacent triphenylphosphine (P (o-tolyl)3), triphen phosphine oxide,
Double (diphenylphosphine) ferrocene (dppf) of 1,1'-, double (diphenyl phosphine) ethane (dppe) of 1,2-or double (diphenylphosphine) propane (dppp) of 1,3-.
Described auxiliary agent is Bu4N+Br-、Bu4N+Cl-、Bu4N+F-Or benzyltriethylammoinium chloride (TEBA).
Compound shown in described formula (I) and Pd catalyst, phosphorus part, alkaline matter, the ratio of amount of the material that feeds intake of auxiliary agent are
1:0.05~0.1:0~0.2:1.5~5:0~2, wherein 0 is meant that to phosphorate and joins in the rate of charge of phosphorus part, auxiliary agent
Body or auxiliary agent, but both can not be 0 simultaneously, and i.e. can not phosphorate part and auxiliary agent simultaneously;The most described formula (I) shownization
Compound and Pd catalyst, phosphorus part, alkaline matter, the ratio of amount of the material that feeds intake of auxiliary agent are 1:0.05~0.1:0.1~0.2:
1.5~5:1~2, particularly preferred 1:0.05:0.1:2:2.
The method of usual described post processing is: after reaction terminates, and reactant liquor evaporated under reduced pressure adds CH2Cl2, more successively through full
And brine It, anhydrous Mg2SO4Being dried, concentrating under reduced pressure, gained concentrate carries out silica gel column chromatography separation, with petroleum ether:
The mixed liquor of ethyl acetate volume ratio 20~1:1 is eluant, collects the eluent containing target compound, removes solvent under reduced pressure also
It is dried, obtains product.
The present invention by mtt assay measure described in 2-aryl-4-methyl ring and pyridine-1 (2H)-one analog derivative IC50Value, pyrrole is non-
Buddhist nun's ketone makees positive control, and result shows that the compounds of this invention has fibrosis biological activity more more preferable than pirfenidone, in preparation
Anti-fibrosis medicine has application prospect.
Advantages of the present invention is mainly reflected in: the synthetic operation of compound of the present invention is simple, and cheaper starting materials is easy to get, instead
Answering mild condition, the response time is shorter, and various substituent groups are had good compatibility.Meanwhile, the compounds of this invention passes through
Mtt assay records IC50Value, with pirfenidone as positive control, result shows that this compounds relatively pirfenidone has preferably
Fibrosis biological activity, lays the foundation for developing new and effective anti-fibrosis medicine.
(4) detailed description of the invention
Below by specific embodiment, the present invention is described further, but protection scope of the present invention is not limited to that.
The reaction result of section Example is listed in the table below 1:
Table 1 section Example 2-aryl-4-methyl ring the synthesis result of pyridine-1 (2H)-one
Embodiment 1
N2Under protective condition, in 25mL two dry mouth flask, it is separately added into substrate 1a (0.48g, 1.5mmol),
Pd(OAc)2(0.017g, 0.075mmol), K2CO3(0.41g, 3mmol), Bu4N+Br-(0.97g, 3mmol),
P(o-tolyl)3(0.046g, 0.15mmol), DMF (5mL), stirring reaction at 110 DEG C, TLC monitors reaction process, time
6h.After reaction terminates, reactant liquor is drained, and adds 30mLCH2Cl2, then wash (20mL × 3) through saturated aqueous common salt, nothing
Water Mg2SO4Being dried, concentrating under reduced pressure, gained concentrate carries out column chromatography for separation, with petroleum ether: ethyl acetate volume ratio 20~1:
The mixed liquor of 1 is eluant, collects the eluent containing target compound, removes solvent under reduced pressure and be dried, obtaining product 2a 0.34
G, productivity 94%.
The physical property of product,1H spectrum,13C spectrum and high-resolution data are as follows:
2-phenyl-4-methyl-5,6,7,8-tetrahydrochysene hexamethylene also [c] pyridine-1 (2H)-one
Yellow liquid:1H NMR(500MHz,CDCl3)δ7.46-7.43(m,2H),7.38-7.35(m,3H),6.98(s,1H),2.59
(t, J=5.5Hz, 2H), 2.51 (d, J=5.5Hz, 2H), 1.99 (d, J=0.6Hz, 3H), 1.81-1.73 (m, 4H);13C
NMR(125MHz,CDCl3)δ161.6,147.6,141.4,131.1,129.0,128.0,127.8,126.7,114.9,26.9,
24.1,21.9,21.8,15.4;HRMS-ESI[M+H]+Calcd for C16H18NO 240.1383, found 240.1388.
Embodiment 2
N2Under protective condition, in 25mL two dry mouth flask, it is separately added into substrate 1a (0.48g, 1.5mmol),
Pd(OAc)2(0.017g, 0.075mmol), K2CO3(0.41g, 3mmol), Bu4N+Br-(0.97g, 3mmol), DMSO (7.5
ML), stirring reaction at 110 DEG C, TLC monitors reaction process, time 12h.After reaction terminates, reactant liquor is drained, and adds
30mLCH2Cl2, then wash (20mL × 3) through saturated aqueous common salt, anhydrous Mg2SO4 is dried, concentrating under reduced pressure, and gained is dense
Contracting thing carries out column chromatography for separation, with petroleum ether: the mixed liquor of ethyl acetate volume ratio 20~1:1, as eluant, is collected containing target
The eluent of compound, removes solvent under reduced pressure and is dried, and obtains product 2a 0.30g, productivity 84%.
Embodiment 3
N2Under protective condition, in 25mL two dry mouth flask, it is separately added into substrate 1a (0.48g, 1.5mmol),
Pd(OAc)2(0.017g, 0.075mmol), K2CO3(0.41g, 3mmol), dppp (0.031g, 0.075mmol), DMAc (5
ML), stirring reaction at 120 DEG C, TLC monitors reaction process, time about 24h.After reaction terminates, reactant liquor is drained, and adds
Enter 30mLCH2Cl2, then wash (20mL × 3) through saturated aqueous common salt, anhydrous Mg2SO4 is dried, concentrating under reduced pressure, gained
Concentrate carries out column chromatography for separation, with petroleum ether: the mixed liquor of ethyl acetate volume ratio 20~1:1, as eluant, is collected containing mesh
The eluent of mark compound, removes solvent under reduced pressure and is dried, obtaining product 2a 0.29g, productivity 82%.
Embodiment 4
N2Under protective condition, in 25mL two dry mouth flask, it is separately added into substrate 1a (0.48g, 1.5mmol),
Pd(OAc)2(0.034g, 0.15mmol), Na2CO3(0.80g, 7.5mmol), dppe (0.12g, 0.3mmol), THF (5
ML), stirring reaction at 60 DEG C, TLC monitors reaction process, time 24h.After reaction terminates, reactant liquor is drained, and adds
30mLCH2Cl2, then wash (20mL × 3) through saturated aqueous common salt, anhydrous Mg2SO4 is dried, concentrating under reduced pressure, and gained is dense
Contracting thing carries out column chromatography for separation, with petroleum ether: the mixed liquor of ethyl acetate volume ratio 20~1:1, as eluant, is collected containing target
The eluent of compound, removes solvent under reduced pressure and is dried, and obtains product 2a 0.33g, productivity 92%.
Embodiment 5
N2Under protective condition, in 25mL two dry mouth flask, it is separately added into substrate 1a (0.48g, 1.5mmol),
Pd(OAc)2(0.017g, 0.075mmol), Cs2CO3(0.98g, 3mmol), Bu4N+Cl-(0.68g, 3mmol),
P(o-tolyl)3(0.046g, 0.15mmol), toluene (5mL), stirring reaction at 100 DEG C, TLC monitors reaction process, time
6h.After reaction terminates, reactant liquor is drained, and adds 30mLCH2Cl2, then wash (20mL × 3) through saturated aqueous common salt, nothing
Water Mg2SO4 is dried, concentrating under reduced pressure, and gained concentrate carries out column chromatography for separation, with petroleum ether: ethyl acetate volume ratio 20~1:
The mixed liquor of 1 is eluant, collects the eluent containing target compound, removes solvent under reduced pressure and be dried, obtaining product 2a 0.32
G, productivity 89%.
Embodiment 6
N2Under protective condition, in 25mL two dry mouth flask, it is separately added into substrate 1a (0.48g, 1.5mmol),
Pd(OAc)2(0.017g, 0.075mmol), Ag2CO3(0.83g, 3mmol), Bu4N+F-(0.78g, 3mmol),
P(o-tolyl)3(0.046g, 0.15mmol), acetonitrile (3mL), stirring reaction at 80 DEG C, TLC monitors reaction process, time
About 24h.After reaction terminates, reactant liquor is drained, and adds 30mLCH2Cl2, then wash (20mL × 3) through saturated aqueous common salt,
Anhydrous Mg2SO4 is dried, concentrating under reduced pressure, and gained concentrate carries out column chromatography for separation, with petroleum ether: ethyl acetate volume ratio
The mixed liquor of 20~1:1 is eluant, collects the eluent containing target compound, removes solvent under reduced pressure and be dried, obtaining product
2a 0.31g, productivity 86%.
Embodiment 7
N2Under protective condition, in 25mL two dry mouth flask, it is separately added into substrate 1a (0.48g, 1.5mmol),
PdCl2(0.013g, 0.075mmol), K2CO3(0.41g, 3mmol), Bu4N+Br-(0.97g, 3mmol), dppf (0.042
G, 0.075mmol), DMF (5mL), stirring reaction at 110 DEG C, TLC monitors reaction process, time about 6h.Reaction knot
Shu Hou, reactant liquor is drained, and adds 30mLCH2Cl2, then wash (20mL × 3) through saturated aqueous common salt, anhydrous Mg2SO4
Being dried, concentrating under reduced pressure, gained concentrate carries out column chromatography for separation, with petroleum ether: the mixing of ethyl acetate volume ratio 20~1:1
Liquid is eluant, collects the eluent containing target compound, removes solvent under reduced pressure and be dried, obtaining product 2a 0.316g, produces
Rate 88%.
Embodiment 8
N2Under protective condition, in 25mL two dry mouth flask, it is separately added into substrate 1a (0.48g, 1.5mmol), chlorination alkene
Propyl group palladium dimer (0.027g, 0.075mmol), K2CO3(0.41g, 3mmol), Bu4N+Br-(0.97g, 3mmol),
P(o-tolyl)3(0.046g, 0.15mmol), DMF (5mL), stirring reaction at 110 DEG C, TLC monitors reaction process, time
About 6h.After reaction terminates, reactant liquor is drained, and adds 30mLCH2Cl2, then wash (20mL × 3) through saturated aqueous common salt,
Anhydrous Mg2SO4 is dried, concentrating under reduced pressure, and gained concentrate carries out column chromatography for separation, with petroleum ether: ethyl acetate volume ratio
The mixed liquor of 20~1:1 is eluant, collects the eluent containing target compound, removes solvent under reduced pressure and be dried, obtaining product
2a 0.32g, productivity 89%.
Embodiment 9
N2Under protective condition, in 25mL two dry mouth flask, it is separately added into substrate 1a (0.48g, 1.5mmol),
Pd(PPh3)4(0.087g, 0.075mmol), K2CO3(0.41g, 3mmol), Bu4N+Br-(0.97g, 3mmol),
P(o-tolyl)3(0.046g, 0.15mmol), DMF (5mL), stirring reaction at 110 DEG C, TLC monitors reaction process, time
About 6h.After reaction terminates, reactant liquor is drained, and adds 30mLCH2Cl2, then wash (20mL × 3) through saturated aqueous common salt,
Anhydrous Mg2SO4 is dried, concentrating under reduced pressure, and gained concentrate carries out column chromatography for separation, with petroleum ether: ethyl acetate volume ratio
The mixed liquor of 20~1:1 is eluant, collects the eluent containing target compound, removes solvent under reduced pressure and be dried, obtaining product
2a 0.305g, productivity 85%.
Embodiment 10
N2Under protective condition, in 25mL two dry mouth flask, it is separately added into substrate 1a (0.48g, 1.5mmol),
PdCl2(PPh3)2(0.053g, 0.075mmol), K2CO3(0.41g, 3mmol), Bu4N+Br-(0.97g, 3mmol),
P(o-tolyl)3(0.046g, 0.15mmol), DMF (5mL), stirring reaction at 110 DEG C, TLC monitors reaction process, time
About 6h.After reaction terminates, reactant liquor is drained, and adds 30mLCH2Cl2, then wash (20mL × 3) through saturated aqueous common salt,
Anhydrous Mg2SO4 is dried, concentrating under reduced pressure, and gained concentrate carries out column chromatography for separation, with petroleum ether: ethyl acetate volume ratio
The mixed liquor of 20~1:1 is eluant, collects the eluent containing target compound, removes solvent under reduced pressure and be dried, obtaining product
2a 0.31g, productivity 86%.
Embodiment 11
N2Under protective condition, in 25mL two dry mouth flask, it is separately added into substrate 1a (0.48g, 1.5mmol),
PdCl2(PPh3)2(0.053g, 0.075mmol), K2CO3(0.31g, 2.25mmol), Bu4N+Br-(0.97g, 3mmol),
PPh3(0.039g, 0.15mmol), ethyl acetate (7.5mL), stirring reaction at 70 DEG C, TLC monitors reaction process, time
About 24h.After reaction terminates, reactant liquor is drained, and adds 30mLCH2Cl2, then wash (20mL × 3) through saturated aqueous common salt,
Anhydrous Mg2SO4 is dried, concentrating under reduced pressure, and gained concentrate carries out column chromatography for separation, with petroleum ether: ethyl acetate volume ratio
The mixed liquor of 20~1:1 is eluant, collects the eluent containing target compound, removes solvent under reduced pressure and be dried, obtaining product
2a 0.32g, productivity 89%.
Embodiment 12
N2Under protective condition, in 25mL two dry mouth flask, it is separately added into substrate 1a (0.48g, 1.5mmol), Pd (OAc)2
(0.017g, 0.075mmol), KOAc (0.74g, 7.5mmol), TEBA (0.68g, 3mmol), PPh3(0.039g,
0.15mmol), DMF (5mL), stirring reaction at 110 DEG C, TLC monitors reaction process, time about 10h.After reaction terminates,
Reactant liquor is drained, and adds 30mLCH2Cl2, then wash (20mL × 3) through saturated aqueous common salt, anhydrous Mg2SO4 is dried,
Concentrating under reduced pressure, gained concentrate carries out column chromatography for separation, with petroleum ether: the mixed liquor of ethyl acetate volume ratio 20~1:1 is for washing
De-agent, collects the eluent containing target compound, removes solvent under reduced pressure and be dried, obtaining product 2a 0.334g, productivity 93%.
Embodiment 13~29
Experimental implementation scheme is with embodiment 1.Weigh reaction substrate 1b~1r (1.5mmol), N respectively2Under protective condition, 25mL
In two dry mouth flasks, it is separately added into substrate 1b~1r (1.5mmol), Pd (OAc)2(0.017g, 0.075mmol),
K2CO3(0.41g, 3mmol), Bu4NBr (0.97g, 3mmol), P (o-tolyl)3(0.046g, 0.15mmol), DMF (5
ML), stirring reaction at 100 DEG C, TLC monitors reaction process.After reaction terminates, reactant liquor is drained, and adds 30mLCH2Cl2,
(20mL × 3) are washed again, anhydrous Mg through saturated aqueous common salt2SO4 is dried, concentrating under reduced pressure, and gained concentrate carries out column chromatography
Separate, with petroleum ether: the mixed liquor of ethyl acetate volume ratio 20~1:1, as eluant, collects the eluent containing target compound,
Remove solvent under reduced pressure and be dried, respectively obtaining product 2b~2r.
The concrete reaction condition of part of embodiment 13~29, yield, productivity are listed in table 2:
The concrete reaction condition of part of table 2 embodiment 13~29, yield, productivity
The physical property of embodiment 13~29 products therefrom,1H spectrum,13C spectrum and high-resolution data are as follows:
2-p-methylphenyl-4-methyl-5,6,7,8-tetrahydrochysene hexamethylene also [c] pyridine-1 (2H)-one
Yellow liquid:1H NMR(500MHz,CDCl3) δ 7.24 (s, 4H), 6.96 (d, J=0.6Hz, 1H), 2.58 (t, J=5.6
Hz, 2H), 2.50 (d, J=5.7Hz, 2H), 2.38 (s, 3H), δ 1.99 (d, J=0.8Hz, 3H), 1.80-1.73 (m, 4H);13C
NMR(125MHz,CDCl3)δ161.7,147.4,138.9,137.6,131.2,129.5,127.8,126.3,114.7,26.8,
24.0,21.9,21.8,21.0,15.3;HRMS-ESI[M+H]+Calcd for C17H20NO 254.1539, found
254.1545.
Tolyl-4-methyl-5,6,7,8-tetrahydrochysene hexamethylene also [c] pyridine-1 (2H)-one between 2-
Yellow liquid:1H NMR(500MHz,CDCl3) δ 7.34 (t, J=8.0Hz, 1H), 7.19-7.14 (m, 3H), 6.97 (d, J
=0.6Hz, 1H), 2.60 (t, J=5.3Hz, 2H), 2.51 (d, J=5.7Hz, 2H), 2.39 (s, 3H), 2.00 (d, J=0.8Hz,
3H),1.82-1.72(m,4H);13C NMR(125MHz,CDCl3)δ161.7,147.5,141.4,139.0,131.2,128.9,
128.6,128.0,127.4,123.6,114.7,26.9,24.1,21.9,21.8,21.3,15.4HRMS-ESI[M+H]+Calcd
for C16H20NO 254.1539, found 254.1529.
2-o-tolyl-4-methyl-5,6,7,8-tetrahydrochysene hexamethylene also [c] pyridine-1 (2H)-one
Yellow liquid:1H NMR(500MHz,CDCl3) δ 7.31-7.26 (m, 3H), 7.14 (d, J=7.5Hz, 1H), 6.83 (s, 1H),
2.60 (t, J=5.4Hz, 2H), 2.52 (t, J=5.6Hz, 2H), 2.14 (s, 3H), 2.00 (s, 3H), 1.83-1.74 (m, 4H);13C
NMR(125MHz,CDCl3)δ161.3,147.5,140.7,135.2,131.0,130.8,128.5,128.0,127.3,126.8,
114.7,26.8,24.0,21.9,21.8,17.6,15.3;HRMS-ESI[M+H]+Calcd for C16H20NO 254.1539,
found 254.1537.
2-rubigan-4-methyl-5,6,7,8-tetrahydrochysene hexamethylene also [c] pyridine-1 (2H)-one
White solid: m.p.135-136 DEG C;1H NMR(500MHz,CDCl3) δ 7.38 (d, J=8.5Hz, 2H), 7.29 (d, J=
8.5Hz, 2H), 6.92 (s, 1H), 2.56 (t, J=5.8Hz, 2H), 2.49 (t, J=5.6Hz, 2H), 1.98 (s, 3H), 1.79-1.71
(m,4H);13C NMR(125MHz,CDCl3)δ161.3,147.8,139.7,133.5,130.5,129.0,127.9,115.2,
26.8,24.0,21.8,21.7,15.3;HRMS-ESI[M+H]+Calcd for C16H17ClNO 274.0993, found
274.0991.
2-Chloro-O-Phenyl-4-methyl-5,6,7,8-tetrahydrochysene hexamethylene also [c] pyridine-1 (2H)-one
Yellow liquid:1H NMR(500MHz,CDCl3)δ7.55-7.52(m,1H),7.39-7.32(m,3H),6.83(s,1H),2.61
(t, J=4.5Hz, 2H), 2.54-2.53 (m, 2H), 2.01 (d, J=0.7Hz, 3H), 1.82-1.76 (m, 4H);13C NMR(125
MHz,CDCl3)δ161.3,148.1,139.0,132.0,130.7,130.4,129.8,129.5,128.2,127.7,115.0,27.0,
24.0,22.0,21.8,15.5;HRMS-ESI[M+H]+Calcd for C16H17ClNO 274.0993, found 274.0983.
2-p-bromophenyl-4-methyl-5,6,7,8-tetrahydrochysene hexamethylene also [c] pyridine-1 (2H)-one
Faint yellow solid: m.p.137-138 DEG C;1H NMR(500MHz,CDCl3) δ 7.58 (d, J=8.7Hz, 2H), 7.26 (d, J=
8.7Hz, 2H), 6.94 (d, J=0.6Hz, 1H), 2.58 (t, J=5.6Hz, 2H), 2.51 (d, J=5.8Hz, 2H), 2.00 (d, J
=0.8Hz, 3H), 1.81-1.73 (m, 4H);13C NMR(125MHz,CDCl3)δ161.4,147.9,140.4,132.2,
130.5,128.4,128.13,121.6,115.3,26.9,24.1,21.9,21.8,15.4.HRMS-ESI[M+H]+Calcd for
C16H17BrNO 318.0494, found 318.0502.
2-is to fluorophenyl-4-methyl-5,6,7,8-tetrahydrochysene hexamethylene also [c] pyridine-1 (2H)-one
Faint yellow solid: m.p.141-143 DEG C;1H NMR(500MHz,CDCl3) δ 7.34-7.31 (m, 2H), 7.11 (t, J=8.6
Hz, 2H), 6.93 (s, 1H), 2.56 (t, J=5.6Hz, 2H), 2.49 (d, J=5.7Hz, 2H), 1.98 (d, J=0.7Hz, 3H),
1.80-1.72(m,4H);13C NMR(125MHz,CDCl3) δ 161.7 (d, J=247.6Hz), 161.5,147.7,137.2 (d,
J=3.2Hz), 130.8,128.3 (d, J=9.0Hz), 127.9,115.8 (d, J=22.8Hz), 115.0,26.8,24.0,21.8,
21.7,15.3;HRMS-ESI[M+H]+Calcd for C16H17FNO 258.1289, found 258.1282.
2-neighbour's fluorophenyl-4-methyl-5,6,7,8-tetrahydrochysene hexamethylene also [c] pyridine-1 (2H)-one
Faint yellow solid: m.p.144-145 DEG C;1H NMR(500MHz,CDCl3)δ7.33-7.25(m,2H),7.17-7.11(m,
2H), 6.84 (s, 1H), 2.54 (t, J=5.8Hz, 2H), 2.45 (d, J=5.6Hz, 2H), 1.92 (d, J=0.7Hz, 3H),
1.75-1.67(m,4H);13C NMR(125MHz,CDCl3) δ 160.9,157.0 (d, J=251.7Hz), 147.8,130.7,
129.7 (d, J=7.8Hz), 128.8,128.6 (d, J=12.8Hz), 127.6,124.2 (d, J=3.7Hz), 116.2 (d, J=
19.7Hz),114.8,26.6,23.7,21.6,21.5,15.0;HRMS-ESI[M+H]+Calcd for C16H17FNO
258.1289, found 258.1297.
2-phenyl-4-methyl-5,6,7,8,9-pentahydro-cycloheptane also [c] pyridine-1 (2H)-one
Yellow liquid:1H NMR(500MHz,CDCl3)δ7.35-7.32(m,2H),7.27-7.24(m,3H),6.89(s,1H),
2.88-2.86(m,2H),2.63-2.61(m,2H),1.95(s,3H),1.82-1.77(m,2H),1.57-1.49(m,4H);13C
NMR(125MHz,CDCl3)δ161.1,153.4,141.3,132.8,131.5,128.4,127.3,126.1,113.6,32.1,
29.7,25.8,25.7,25.0,16.3;HRMS-ESI[M+H]+Calcd for C17H20NO 254.1539, found
254.1536.
2-p-methylphenyl-4-methyl-5,6,7,8,9-pentahydro-cycloheptane also [c] pyridine-1 (2H)-one
Yellow solid: m.p.134-135 DEG C;1H NMR(500MHz,CDCl3)δ7.22(s,4H),6.94(s,1H),2.93-2.91(m,
2H), 2.70-2.68 (m, 2H), 2.36 (s, 3H), 2.02 (d, J=0.8Hz, 3H), 1.88-1.84 (m, 2H), 1.63-1.55 (m,
4H);13C NMR(125MHz,CDCl3)δ161.6,153.6,139.0,137.4,133.1,132.0,129.3,126.1,113.8,
32.4,30.0,26.0,25.9,25.3,20.8,16.6;HRMS-ESI[M+H]+Calcd for C18H22NO 268.1696,
found 268.1703.
2-rubigan-4-methyl-5,6,7,8,9-pentahydro-cycloheptane also [c] pyridine-1 (2H)-one
Yellow solid: m.p.134-135 DEG C;1H NMR(500MHz,CDCl3) δ 7.29 (d, J=8.7Hz, 2H), 7.22 (d, J=
8.7Hz, 2H), 6.85 (s, 1H), 2.84-2.82 (m, 2H), 2.63-2.60 (m, 2H), 1.95 (d, J=0.5Hz, 3H),
1.81-1.76(m,2H),1.55-1.46(m,4H);13C NMR(125MHz,CDCl3)δ161.1,153.8,139.7,133.1,
132.9,131.1,128.6,127.6,114.1,32.1,29.8,25.8,25.7,25.0,16.4;HRMS-ESI[M+H]+Calcd
for C17H19ClNO 288.1150, found 288.1161.
2-phenyl-4-methyl-5,6,7-three hydrogen Pentamethylene. also [c] pyridine-1 (2H)-one
Yellow liquid:1H NMR(500MHz,CDCl3) δ 7.46-7.43 (m, 2H), 7.38-7.35 (m, 3H), 7.00 (d, J=0.7
Hz, 1H), 2.89 (t, J=7.6Hz, 2H), 2.83 (t, J=7.8Hz, 2H), 2.14-2.07 (m, 2H), 2.03 (d, J=0.7Hz,
3H);13C NMR(125MHz,CDCl3)δ160.1,155.7,141.3,133.8,132.2,129.0,127.9,126.7,113.1,
32.9,30.5,23.1,15.2;HRMS-ESI[M+H]+Calcd for C15H16NO 226.1226, found 226.1220.
2-p-methylphenyl-4-methyl-5,6,7-three hydrogen Pentamethylene. also [c] pyridine-1 (2H)-one
Yellow liquid:1H NMR(500MHz,CDCl3) δ 7.24 (s, 4H), 6.99 (d, J=0.6Hz, 1H), 2.89 (t, J=7.4
Hz, 2H), 2.83 (t, J=7.4Hz, 2H), 2.38 (s, 3H), 2.13-2.07 (m, 2H), 2.03 (d, J=0.6Hz, 3H);13C
NMR(125MHz,CDCl3)δ160.1,155.6,138.7,137.7,133.9,132.1,129.5,126.4,113.0,32.9,
30.4,23.0,21.0,15.1;HRMS-ESI[M+H]+Calcd for C16H18NO 240.1388, found 240.1396
2-rubigan-4-methyl-5,6,7-three hydrogen Pentamethylene. also [c] pyridine-1 (2H)-one
Yellow solid: m.p.157-158 DEG C;1H NMR(500MHz,CDCl3) δ 7.42 (d, J=8.6Hz, 2H), 7.31 (d, J=
8.6Hz, 2H), 6.97 (d, J=0.7Hz, 1H), 2.89 (t, J=7.5Hz, 2H), 2.84 (t, J=7.4Hz, 2H), 2.14-2.08
(m, 2H), 2.04 (d, J=0.7Hz, 3H);NMR(125MHz,CDCl3)δ160.0,156.1,139.7,133.8,133.4,
132.4,129.2,128.2,113.6,33.0,30.5,23.1,15.3;HRMS-ESI[M+H]+Calcd for C15H15ClNO
260.0837, found 260.0842.
2-phenyl-4-methyl-5,6,7,8,9,10-hexahydro cyclooctane also [c] pyridine-1 (2H)-one
Yellow liquid:1H NMR(500MHz,CDCl3)δ7.47-7.44(m,2H),7.39-7.35(m,3H),7.02(s,1H),
2.85-2.83 (m, 2H), 2.74-2.71 (m, 2H), 2.07 (d, J=0.6Hz, 3H), 1.74-1.68 (m, 4H), 1.50-1.43 (m,
4H);13C NMR(125MHz,CDCl3)δ161.3,150.6,141.6,132.2,131.2,128.9,127.8,126.7,114.2,
29.1,29.0,28.2,26.8,26.1,25.7,16.1;HRMS-ESI[M+H]+Calcd for C18H22NO 268.1696,
found 268.1700.
2-p-methylphenyl-4-methyl-5,6,7,8,9,10-hexahydro cyclooctane also [c] pyridine-1 (2H)-one
Yellow solid: m.p.118-119 DEG C;1H NMR(500MHz,CDCl3)δ7.26-7.22(m,4H),6.99(s,1H),
2.83-2.81(m,2H),2.71-2.69(m,2H),2.37(s,3H),2.05(s,3H),1.73-1.67(m,4H),1.49-1.42(m,
4H);13C NMR(125MHz,CDCl3)δ161.2,150.3,139.0,137.4,132.3,131.0,129.4,126.3,113.9,
29.0,28.9,28.1,26.7,26.0,25.6,20.9,16.0;HRMS-ESI[M+H]+Calcd for C19H24NO
282.1852, found 282.1855.
2-rubigan-4-methyl-5,6,7,8,9,10-hexahydro cyclooctane also [c] pyridine-1 (2H)-one
Yellow solid: m.p.128-129 DEG C;1H NMR(500MHz,CDCl3)δ7.32-7.30(m,2H),7.27-7.25(m,2H),
6.91(s,1H),2.76-2.73(m,2H),2.65-2.62(m,2H),1.99(s,3H),1.62-1.59(m,4H),1.42-1.35(m,
4H);13C NMR(125MHz,CDCl3)δ160.7,150.5,139.7,133.1,131.4,130.9,128.7,127.7,114.3,
28.8,28.7,27.9,26.5,25.8,25.4,15.8;HRMS-ESI[M+H]+Calcd for C18H21ClNO 302.1306,
found 302.1301.
Embodiment 30
2-aryl-4-methyl ring pyridine-1 (2H)-one class derivative compound fibrosis biological activity determination
Choose the embryo fibroblast NIH of mice3T3For object of study, with pirfenidone as positive control, use MTT
Method investigates the 2-aryl-4-methyl ring of synthesis pyridine-1 (2H)-one analog derivative to NIH3T3The inhibitory action of cell proliferation is strong
Degree, passes through IC50Value can compare the biological activity difference between pirfenidone and this series compound.
Fibrosis biological activity determination embodiment is as follows:
Employing MTT colorimetry, the mouse embryo fibroblasts DMEM culture medium containing 10% calf serum, at 37 DEG C,
Containing 5% CO2Humidification cell culture incubator is cultivated.By NIH3T3Cell is inoculated in 96 orifice plates, every hole 10000 cell,
Continue to cultivate 4h.After cell attachment, change into containing variable concentrations compound and pirfenidone containing 5% the training of calf serum
Supporting base, each concentration arranges 3 multiple holes.After cultivating 72 hours, the MTT solution (20uL) of addition 5% in every hole, 4
After hour, by MTT sucking-off, every hole adds MTT lysate DMSO (100uL), treats that MTT is completely dissolved.15min
After, under 490nm, use microplate reader to measure OD value, process data with OriginPro 8.0 and obtain pirfenidone and 2-virtue
Base-4-methyl ring the IC of pyridine-1 (2H)-one analog derivative50Value, the results are shown in Table 3.
Table 3 the compounds of this invention and pirfenidone fibrosis biological activity determination result
Conclusion as can be drawn from Table 3:
(1) the fibrosis biological activity of this series 2-aryl-4-methyl ring pyridine-1 (2H)-one analog derivative is superior to the non-Buddhist nun of pyrrole
Ketone;
(2) substituent group of 2-phenyl ring has certain promotion to biological activity, and 2e (R=p-Cl) activity is the highest, for the 114 of pirfenidone
Times;
(3), when R substituent is halogen, Cl is better than Br and F, Cl the most relatively CH3Good;
(4) prove the fibrosis biological activity being incorporated to be favorably improved pirfenidone of ring simultaneously, obtain series of new
There is fibrosis biological activity 2-aryl-4-methyl ring pyridine-1 (2H)-one class derivative compound.
Claims (8)
1. the 2-aryl-4-methyl ring shown in a formula (II) pyridine-1 (2H)-one analog derivative:
In formula (II):
R is hydrogen, methyl, chlorine, bromine or fluorine;
N is 1,2,3 or 4.
2. 2-aryl-4-methyl ring as claimed in claim 1 pyridine-1 (2H)-one analog derivative, it is characterised in that described
2-aryl-4-methyl ring and pyridine-1 (2H)-one analog derivative be one of compound shown in formula (2a)~(2r):
3. 2-aryl-4-methyl ring as claimed in claim 1 a synthetic method for pyridine-1 (2H)-one analog derivative, its
Being characterised by, described synthetic method is:
N2Under protective condition, with the compound shown in formula (I) as raw material, in organic solvent, alkaline matter, Pd catalyst,
In the presence of phosphorus part, auxiliary agent, reacting 6~24h in 60~120 DEG C, reactant liquor is post-treated afterwards, obtains producing shown in formula (II)
Thing;
Described organic solvent is toluene, acetonitrile, THF, ethyl acetate, DMSO, DMF or DMAc;
Described alkaline matter is triethylamine, potassium acetate, potassium carbonate, sodium carbonate, Disilver carbonate, cesium carbonate or potassium tert-butoxide;
Described Pd catalyst is Pd (OAc)2、PdCl2(PPh3)2、PdCl2、Pd(PPh3)4Or chlorination Allylpalladium dimer;
Described phosphorus part is tributylphosphine, triphenylphosphine, adjacent triphenylphosphine, triphen phosphine oxide, 1,1'-double (diphenylphosphine) two cyclopentadienyl
Double (diphenyl phosphine) ethane of ferrum, 1,2-or double (diphenylphosphine) propane of 1,3-;
Described auxiliary agent is Bu4N+Br-、Bu4N+Cl-、Bu4N+F-Or benzyltriethylammoinium chloride;
Compound shown in described formula (I) and Pd catalyst, phosphorus part, alkaline matter, the ratio of amount of the material that feeds intake of auxiliary agent are
1:0.05~0.1:0~0.2:1.5~5:0~2, wherein in the rate of charge of phosphorus part, auxiliary agent 0 be meant that do not phosphorate part or
Auxiliary agent, but both can not be 0 simultaneously, and i.e. can not phosphorate part and auxiliary agent simultaneously;
In formula (I) or formula (II),
R is hydrogen, methyl, chlorine, bromine or fluorine;
N is 1,2,3 or 4.
4. synthetic method as claimed in claim 3, it is characterised in that the volumetric usage of described organic solvent is with formula (I) institute
Show that the amount of the material of compound is calculated as 2~5mL/mmol.
5. synthetic method as claimed in claim 3, it is characterised in that compound shown in described formula (I) and Pd catalyst,
Phosphorus part, alkaline matter, the ratio of amount of the material that feeds intake of auxiliary agent are 1:0.05~0.1:0.1~0.2:1.5~5:1~2.
6. synthetic method as claimed in claim 3, it is characterised in that compound shown in described formula (I) and Pd catalyst,
Phosphorus part, alkaline matter, the ratio of amount of the material that feeds intake of auxiliary agent are 1:0.05:0.1:2:2.
7. synthetic method as claimed in claim 3, it is characterised in that the method for described post processing is: after reaction terminates,
Reactant liquor evaporated under reduced pressure, adds CH2Cl2, then wash through saturated aqueous common salt successively, anhydrous Mg2SO4It is dried, concentrating under reduced pressure,
Gained concentrate carries out silica gel column chromatography separation, with petroleum ether: the mixed liquor of ethyl acetate volume ratio 20~1:1 as eluant,
Collect the eluent containing target compound, remove solvent under reduced pressure and be dried, obtaining product.
8. 2-aryl-4-methyl ring as claimed in claim 1 pyridine-1 (2H)-one analog derivative are preparing anti-fibrosis medicine
In application.
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CN113583012B (en) * | 2021-08-05 | 2022-05-27 | 江西省科学院应用化学研究所 | Synthesis method of pyrano [4,3-b ] pyridine-2, 7-dione compound |
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