CN104610265A - Compound and preparation method thereof - Google Patents
Compound and preparation method thereof Download PDFInfo
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- CN104610265A CN104610265A CN201410853333.9A CN201410853333A CN104610265A CN 104610265 A CN104610265 A CN 104610265A CN 201410853333 A CN201410853333 A CN 201410853333A CN 104610265 A CN104610265 A CN 104610265A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention relates to the technical field of medicines, in particular to a compound and a preparation method thereof. The compound adopts a structure shown in the formula (I) (shown in the description), and has excellent anti-tumor activity based on pharmacological experiments. Besides, the invention provides a method for preparing the compounds. The method has the advantages of few reaction steps, mild reaction conditions and high yield.
Description
Technical field
The present invention relates to medical art, particularly relate to a kind of compound and preparation method thereof.
Background technology
Malignant tumour is one of persistent ailment of serious threat human life health, and how prevention and therapy tumour has become one of key subjects of main research in bio-science field.Traditional antitumor drug can kill normal tissue cell while killing tumour cell, usually causes severe side effect.In recent years along with the development of molecular biology, molecular weight tumor and molecular pharmacology, the research of antitumor drug is by the future development of conventional cell cytotoxic drug to molecular targeted antitumor drug.
Generation, the development of research discovery most of malignant tumour are all relevant with cell cycle regulating dysfunction, and the overactivity of cyclin dependent kinase (cyclin-dependent kinases, CDKs) causes a disorderly major reason.
CDKs is a class serine/threonine kinase, and its relative molecular weight (comprises 200 to 400 amino acid) between 35kD to 45KD.The CDK family member confirmed in human body has 13 (CDK1 ~ 13), at present in the structural research of CDKs, the most extensive with the research of CDK2.With other kinases unlike, independent CDKs catalytic subunit and non-activity, only have the mixture formed after combining with cyclin (cyclins) that the activity of protein kinase can be shown.The substrate phosphorylation that tool activated CDK/cyclin mixture is different according to different cyclin catalytic subunit catalysis, thus drive cell to complete by the switching process of G1-S-G2-M each phase, sequentially complete synthesis and the mitotic division of DNA, promote growth and the propagation of cell.Meanwhile, CDKs also can combine with CDKs supressor (CDI) and play down regulation, T suppression cell cycle progression, stops cell fission.
It is reported, more than the variation that there is Rb protein kinase pathways in the human tumor cell of 90%.These variations change relevant with expression imbalance with the expression level of CDK2, CDK4, CDK6, cyclin D, Rb albumen and p16 gene family etc.In the cancer cells such as esophageal squamous cell carcinoma, colorectal carcinoma, lung cancer, prostate cancer, oral carcinoma, mammary cancer, the expression of CDK1 apparently higher than normal tissue cell, and most is expressed as positive correlation with Cyclin B1.CDK2 and CDK4 has high expression level in the cancer cells such as liver cancer, carcinoma of the pancreas, ovarian cancer.The chromosome translocation of CDK6 gene and gene amplification all can cause CDK6 overexpression, and lymphoma, neurospongioma and squama cancer are considered to related to this.Because CDKs plays a crucial role in the Proliferation and apoptosis of regulate tumor cell, by the activity of CDKs in optionally Tumor suppression tissue, can play a positive role to the treatment of the malignant proliferative disease such as tumour, so become one of hot fields of oncotherapy and development of new chemotherapeutics to the screening of CDKs micromolecular inhibitor with research.Over the past two years, CDKs inhibitor achieved breakthrough progress in clinical study.In April, 2013, due to the good behaviour in the clinical trial of mammary cancer, the CDK4/6 inhibitor PD-0332991 of Pfizer's research and development obtains FDA important breakthrough medicine and assert, has entered the III phase at present clinical, has been expected to granted listing in 2015.Therefore, the CDKs micromolecular inhibitor of development of new has broad prospects.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is to provide a kind of compound and preparation method thereof.Compound provided by the invention has the structure shown in formula (I), and it has good CDK2 kinase inhibiting activity, can block the G2/M phase in tumor cell cycle and induce its apoptosis; By scientific research, determine the method for synthesis the compounds of this invention, the method has the advantage that reactions steps is few, reaction conditions is gentle, yield is high.
Object of the present invention is achieved through the following technical solutions.
The invention provides the compound that one has structure shown in formula (I):
Wherein R
1, R
2represent hydrogen, alkyl, cyano group, halogen, haloalkyl, hydroxyl, alkoxyl group independently of one another;
Ar is selected from phenyl, and wherein phenyl can optionally by one or more R
3replace, R
3can be hydrogen, alkyl, cyano group, halogen, haloalkyl, hydroxyl, alkoxyl group;
Alkyl is the straight or branched saturated hydrocarbyl with 1-6 carbon atom; Or for having the cyclic saturated hydrocarbon base of 3-6 carbon atom; Or for connecting the cyclic saturated hydrocarbon base with 3-6 carbon atom with the straight or branched saturated hydrocarbyl of 1-6 carbon atom;
Halogen is the substituting group being selected from fluorine, chlorine, bromine or iodine;
Haloalkyl is the straight or branched saturated hydrocarbyl with 1-6 carbon atom, or for having the cyclic saturated hydrocarbon base of 3-6 carbon atom, or for connecting the cyclic saturated hydrocarbon base with 3-6 carbon atom with the straight or branched saturated hydrocarbyl of 1-6 carbon atom; Wherein one or more carbon atoms are optionally substituted with one or more halogen atoms;
Alkoxyl group is the straight or branched saturated hydrocarbyl with 1-6 carbon atom; Or for having the cyclic saturated hydrocarbon base of 3-6 carbon atom; Or for connecting the cyclic saturated hydrocarbon base with 3-6 carbon atom with the straight or branched saturated hydrocarbyl of 1-6 carbon atom; Wherein each carbon atom is optionally replaced by oxygen.
Preferred version of the present invention is:
Wherein R
1, R
2represent hydrogen, alkyl independently of one another;
Ar is selected from phenyl, and wherein phenyl can optionally by one or two R
3replace, R
3can be hydrogen, halogen, haloalkyl, alkoxyl group.
Another preferred version of the present invention is:
Wherein R
1, R
2represent hydrogen, methyl independently of one another;
Ar is selected from phenyl, and wherein phenyl can optionally by one or two R
3replace, R
3can be hydrogen, chlorine, fluorine, trifluoromethyl, methoxyl group.
Preferably, compound provided by the invention is:
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-benzamide (I-1)
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-4-chlorobenzamide (I-2)
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-4-fluorobenzamide (I-3)
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-4-methoxy benzamide (I-4)
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-4-trifluoromethyl benzamide (I-5)
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-2,6-dichloro-benzamides (I-6)
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-2,6-difluorobenzamides (I-7)
N-(3-(6-(2-5-methyl-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-2,6-dichloro-benzamides (I-8)
N-(3-(6-(2-6-methyl-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-2,6-dichloro-benzamides (I-9).
The preparation method of compound provided by the invention is as follows:
Wherein R
1, R
2represent hydrogen, alkyl independently of one another;
Ar is selected from phenyl, and wherein phenyl can optionally by one or two R
3replace, R
3can be hydrogen, halogen, haloalkyl, alkoxyl group.
There is halogenating reaction and obtain Compound I-b in Compound I-a and 2-hydroxyl-5-nitropyridine, then through the reduction of palladium carbon, obtain Compound I further with the condensation of substituted aryl formic acid under alkali effect.
Chloro azolopyrimidines I-a is under mineral alkali and cuprous iodide effect, and 2-hydroxyl-5-nitropyridine generation substitution reaction generates Compound I-b; Compound I-b obtains Compound I-c through palladium hydrocarbonize reduction nitro; Finalization compound I-c and carboxylic acid compound condensation obtain I.
The alkali that Compound I-a uses when preparing Compound I-b is salt of wormwood, sodium carbonate, cesium carbonate, sodium methylate, sodium ethylate, potassium tert.-butoxide or sodium tert-butoxide, preferred cesium carbonate.
When Compound I-a prepares Compound I-b, temperature of reaction is 25-110 DEG C, preferably 75 DEG C.
The invention provides the compound that one has structure shown in formula (I), this compounds has good anti-tumor activity.In addition, present invention also offers the method for this compounds of preparation, the method has the advantage that reactions steps is few, reaction conditions is gentle, yield is high.
Embodiment
Further illustrate the present invention by following examples, following examples, only for more specifically the preferred embodiment of the present invention being described, being not used in and limiting technical scheme of the present invention.
Embodiment 1
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl) benzamide (I-1)
(1) preparation of 2-((2-5-nitropyridine base) oxygen base)-7H-pyrrolo-[2,3-d] pyrimidine
2-chloro-7H-pyrrolo-[2,3-d] pyrimidine 15.3g (100mmol), 2-hydroxyl-5-nitropyridine 15.4g (110mmol), cesium carbonate 65.2g (200mmol), cuprous iodide 0.2g and dry DMF 200ml is added in 500ml three-necked bottle.Be cooled to room temperature after being warming up to 75 DEG C of stirring 3h, reaction solution slowly poured in 1000ml water, separates out a large amount of gray solid.Leave standstill, suction filtration, filter cake 50ml water washing, 60 DEG C of vacuum-dryings obtain 2-((2-5-nitropyridine base) oxygen base)-7H-pyrrolo-[2,3-d] pyrimidine 22g, yield 86%.MS[M+H]+258.1。
(2) preparation of 2-((2-5-aminopyridine base) oxygen base)-7H-pyrrolo-[2,3-d] pyrimidine
2-((2-5-nitropyridine base) oxygen base)-7H-pyrrolo-[2,3-d] pyrimidine 22g, 10% palladium carbon 2.2g and methyl alcohol 350ml is added in the mono-neck bottle of the 500ml that hydrogen gas bag is housed.Hydrogen pump drainage three times, room temperature reaction.TLC monitors raw material and disappears, and filter, filtrate reduced in volume obtains 2-((2-5-aminopyridine base) oxygen base)-7H-pyrrolo-[2,3-d] pyrimidine crude product 20g, yield 91%.MS[M+H]+228.1。
(3) preparation of N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl) benzamide
Add in the mono-neck bottle of 50ml 2-((2-5-aminopyridine base) oxygen base)-7H-pyrrolo-[2,3-d] pyrimidine 91mg (0.4mmol), phenylformic acid 61mg (0.5mmol), I-hydroxybenzotriazole (HOBt) 54mg (0.4mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI) 96mg (0.5mmol) and dry DMF 10ml.Room temperature reaction, TLC monitors raw material and disappears, and is poured into by reaction solution in 50ml water, separates out white solid.Leave standstill, suction filtration, filter cake crude product obtains compound (I-1) 95mg through column chromatography (moving phase: ethanol/methylene=1/20), yield 72%.MS[M+H]+332.1。
1H-NMR[300MHz,DMSO-d6]:δ6.5(1H,d,J＝7.4Hz,Pyridine),6.7(1H,s,Pyridine),6.9(2H,d,ArH),7.1(1H,d,J＝7.4Hz,Pyridine),7.5(3H,m,ArH),7.6(1H,s,ArH),8.1(2H,d,ArH),9.0(1H,s,ArH),9.2(1H,s,-NHCO-)
Embodiment 2
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl) the chloro-benzamide of-4-(I-2)
Preparation method is similar to compound (I-1), with 2-((2-5-aminopyridine base) oxygen base)-7H-pyrrolo-[2,3-d] pyrimidine 91mg (0.4mmol) and 4-chloro-benzoic acid 78mg (0.5mmol) is raw material, obtain compound (I-2) 110mg, yield 75%.MS [M+H]+366.1。
1H-NMR[300MHz,DMSO-d6]:δ6.5(1H,d,J＝7.4Hz,Pyridine),6.7(1H,s,Pyridine),6.9(2H,d,ArH),7.1(1H,d,J＝7.4Hz,Pyridine),7.5(2H,d,J＝8.4Hz,ArH),7.6(1H,s,ArH),7.9(2H,d,J＝8.4Hz,ArH),9.0(1H,s,ArH),9.2(1H,s,-NHCO-)
Embodiment 3
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-4-fluorobenzamide (I-3)
Preparation method is similar to compound (I-1), with 2-((2-5-aminopyridine base) oxygen base)-7H-pyrrolo-[2,3-d] pyrimidine 91mg (0.4mmol) and 4-fluorobenzoic acid 70mg (0.5mmol) is raw material, obtain compound (I-3) 111mg, yield 80%.MS[M+H]+350.1。
1H-NMR[300MHz,DMSO-d6]:δ6.5(1H,d,J＝7.4Hz,Pyridine),6.7(1H,s,Pyridine),6.9(2H,d,ArH),7.1(1H,d,J＝7.4Hz,Pyridine),7.4(2H,d,J＝8.4Hz,ArH),7.6(1H,s,ArH),8.1(2H,d,J＝8.4Hz,ArH),9.0(1H,s,ArH),9.2(1H,s,-NHCO-)
Embodiment 4
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-4-methoxy benzamide (I-4)
Preparation method is similar to compound (I-1), with 2-((2-5-aminopyridine base) oxygen base)-7H-pyrrolo-[2,3-d] pyrimidine 91mg (0.4mmol) and 4-methoxybenzoic acid 76mg (0.5mmol) is raw material, obtain compound (I-4) 98mg, yield 68%.MS[M+H]+362.1。
1H-NMR[300MHz,DMSO-d6]:δ3.8(3H,s,-OCH
3),6.5(1H,d,J＝7.4Hz,Pyridine),6.7(1H,s,Pyridine),6.9(2H,d,ArH),7.1(1H,d,J＝7.4Hz,Pyridine),7.2(2H,d,J＝8.4Hz,ArH),7.6(1H,s,ArH),7.9(2H,d,J＝8.4Hz,ArH),9.0(1H,s,ArH),9.2(1H,s,-NHCO-)
Embodiment 5
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-4-trifluoromethyl yl-benzamide (I-5)
Preparation method is similar to compound (I-1), with 2-((2-5-aminopyridine base) oxygen base)-7H-pyrrolo-[2,3-d] pyrimidine 91mg (0.4mmol) and 4-trifluoromethylbenzoic acid 95mg (0.5mmol) is raw material, obtain compound (I-5) 113mg, yield 71%.MS[M+H]+400.1。
1H-NMR[300MHz,DMSO-d6]:δ6.5(1H,d,J＝7.4Hz,Pyridine),6.7(1H,s,Pyridine),6.9(2H,d,ArH),7.1(1H,d,J＝7.4Hz,Pyridine),7.6(1H,s,ArH),7.7(2H,d,J＝8.4Hz,ArH),8.1(2H,d,J＝8.4Hz,ArH),9.0(1H,s,ArH),9.2(1H,s,-NHCO-)
Embodiment 6
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-2,6-dichloro-benzamides (I-6)
Preparation method is similar to compound (I-1), with 2-((2-5-aminopyridine base) oxygen base)-7H-pyrrolo-[2,3-d] pyrimidine 91mg (0.4mmol) and 2,6-dichlorobenzoic acid 96mg (0.5mmol) is raw material, obtain compound (I-6) 119mg, yield 75%.MS[M+H]+400.1。
1H-NMR[300MHz,DMSO-d6]:δ6.5(1H,d,J＝7.4Hz,Pyridine),6.7(1H,s,Pyridine),6.9(2H,d,ArH),7.1(1H,d,J＝7.4Hz,Pyridine),7.5(2H,d,ArH),7.6(1H,s,ArH),7.9(1H,t,ArH),9.0(1H,s,ArH),9.2(1H,s,-NHCO-)
Embodiment 7
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-2,6-difluorobenzamides (I-7)
Preparation method is similar to compound (I-1), with 2-((2-5-aminopyridine base) oxygen base)-7H-pyrrolo-[2,3-d] pyrimidine 91mg (0.4mmol) and 2,6-difluoro-benzoic acid 79mg (0.5mmol) is raw material, obtain compound (I-7) 106mg, yield 72%.MS[M+H]+368.1。
1H-NMR[300MHz,DMSO-d6]:δ6.5(1H,d,J＝7.4Hz,Pyridine),6.7(1H,s,Pyridine),6.9(2H,d,ArH),7.1(1H,d,J＝7.4Hz,Pyridine),7.2(2H,d,ArH),7.6(1H,s,ArH),7.7(1H,t,ArH),9.0(1H,s,ArH),9.2(1H,s,-NHCO-)
Embodiment 8
N-(3-(6-(2-5-methyl-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-2,6-dichloro-benzamides (I-8)
(1) preparation of 2-((2-5-nitropyridine base) oxygen base)-5-methyl-7H-pyrrolo-[2,3-d] pyrimidine
The chloro-5-methyl of 2--7H-pyrrolo-[2,3-d] pyrimidine 1.67g (10mmol), 2-hydroxyl-5-nitropyridine 1.54g (11mmol), cesium carbonate 6.52g (20mmol), cuprous iodide 0.02g and dry DMF 20ml is added in 500ml three-necked bottle.Be cooled to room temperature after being warming up to 75 DEG C of stirring 3h, reaction solution slowly poured in 100ml water, separates out a large amount of gray solid.Leave standstill, suction filtration, filter cake 5ml water washing, 60 DEG C of vacuum-dryings obtain 2-((2-5-nitropyridine base) oxygen base)-5-methyl-7H-pyrrolo-[2,3-d] pyrimidine 2.02g, yield 75%.MS[M+H]+272.1。
(2) preparation of 2-((2-5-aminopyridine base) oxygen base)-5-methyl-7H-pyrrolo-[2,3-d] pyrimidine
2-((2-5-nitropyridine base) oxygen base)-5-methyl-7H-pyrrolo-[2,3-d] pyrimidine 2.02g, 10% palladium carbon 0.20g and methyl alcohol 35ml is added in the mono-neck bottle of the 50ml that hydrogen gas bag is housed.Hydrogen pump drainage three times, room temperature reaction.TLC monitors raw material and disappears, and filter, filtrate reduced in volume obtains 2-((2-5-aminopyridine base) oxygen base)-5-methyl-7H-pyrrolo-[2,3-d] pyrimidine crude product 1.63g, yield 90%.MS[M+H]+242.1。
(3) preparation of N-(3-(6-(2-5-methyl-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-2,6-dichloro-benzamides
2-((2-5-aminopyridine base) oxygen base)-5-methyl-7H-pyrrolo-[2 is added in the mono-neck bottle of 50ml, 3-d] pyrimidine 96mg (0.4mmol), 2,6-dichlorobenzoic acid 96mg (0.5mmol), I-hydroxybenzotriazole (HOBt) 54mg (0.4mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI) 96mg (0.5mmol) and dry DMF 10ml.Room temperature reaction, TLC monitors raw material and disappears, and is poured into by reaction solution in 50ml water, separates out white solid.Leave standstill, suction filtration, filter cake crude product obtains compound (I-8) 115mg through column chromatography (moving phase: ethanol/methylene=1/20), yield 70%.MS[M+H]+414.1。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH
3),6.3(1H,s,ArH),6.5(1H,d,J＝7.4Hz, Pyridine),6.7(1H,s,Pyridine),7.1(1H,d,J＝7.4Hz,Pyridine),7.5(2H,d,ArH),7.6(1H,s,ArH),7.9(1H,t,ArH),9.0(1H,s,ArH),9.2(1H,s,-NHCO-)
Embodiment 9
N-(3-(6-(2-6-methyl-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-2,6-dichloro-benzamides (I-9)
(1) preparation of 2-((2-5-nitropyridine base) oxygen base)-6-methyl-7H-pyrrolo-[2,3-d] pyrimidine
The chloro-6-methyl of 2--7H-pyrrolo-[2,3-d] pyrimidine 1.67g (10mmol), 2-hydroxyl-5-nitropyridine 1.54g (11mmol), cesium carbonate 6.52g (20mmol), cuprous iodide 0.02g and dry DMF 20ml is added in 500ml three-necked bottle.Be cooled to room temperature after being warming up to 75 DEG C of stirring 3h, reaction solution slowly poured in 100ml water, separates out a large amount of gray solid.Leave standstill, suction filtration, filter cake 5ml water washing, 60 DEG C of vacuum-dryings obtain 2-((2-5-nitropyridine base) oxygen base)-6-methyl-7H-pyrrolo-[2,3-d] pyrimidine 2.10g, yield 78%.MS[M+H]+272.1。
(2) preparation of 2-((2-5-aminopyridine base) oxygen base)-6-methyl-7H-pyrrolo-[2,3-d] pyrimidine
2-((2-5-nitropyridine base) oxygen base)-6-methyl-7H-pyrrolo-[2,3-d] pyrimidine 2.10g, 10% palladium carbon 0.20g and methyl alcohol 35ml is added in the mono-neck bottle of the 50ml that hydrogen gas bag is housed.Hydrogen pump drainage three times, room temperature reaction.TLC monitors raw material and disappears, and filter, filtrate reduced in volume obtains 2-((2-5-aminopyridine base) oxygen base)-6-methyl-7H-pyrrolo-[2,3-d] pyrimidine crude product 1.72g, yield 95%.MS[M+H]+242.1。
(3) preparation of N-(3-(6-(2-6-methyl-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-2,6-dichloro-benzamides
2-((2-5-aminopyridine base) oxygen base)-6-methyl-7H-pyrrolo-[2 is added in the mono-neck bottle of 50ml, 3-d] pyrimidine 96mg (0.4mmol), 2,6-dichlorobenzoic acid 96mg (0.5mmol), I-hydroxybenzotriazole (HOBt) 54mg (0.4mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI) 96mg (0.5mmol) and dry DMF 10ml.Room temperature reaction, TLC monitors raw material and disappears, and is poured into by reaction solution in 50ml water, separates out white solid.Leave standstill, suction filtration, filter cake crude product obtains compound (I-9) 120mg through column chromatography (moving phase: ethanol/methylene=1/20), yield 73%.MS[M+H]+414.1。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH
3),6.1(1H,s,ArH),6.5(1H,d,J＝7.4Hz,Pyridine),6.7(1H,s,Pyridine),7.1(1H,d,J＝7.4Hz,Pyridine),7.5(2H,d,ArH),7.6(1H,s,ArH),7.9(1H,t,ArH),9.0(1H,s,ArH),9.2(1H,s,-NHCO-)。
Claims (9)
1. one kind has the compound of structure shown in formula (I):
Wherein R
1, R
2represent hydrogen, alkyl, cyano group, halogen, haloalkyl, hydroxyl, alkoxyl group independently of one another;
Ar is selected from phenyl, and wherein phenyl can optionally by one or more R
3replace, R
3can be hydrogen, alkyl, cyano group, halogen, haloalkyl, hydroxyl, alkoxyl group;
Alkyl is the straight or branched saturated hydrocarbyl with 1-6 carbon atom; Or for having the cyclic saturated hydrocarbon base of 3-6 carbon atom; Or for connecting the cyclic saturated hydrocarbon base with 3-6 carbon atom with the straight or branched saturated hydrocarbyl of 1-6 carbon atom;
Halogen is the substituting group being selected from fluorine, chlorine, bromine or iodine;
Haloalkyl is the straight or branched saturated hydrocarbyl with 1-6 carbon atom, or for having the cyclic saturated hydrocarbon base of 3-6 carbon atom, or for connecting the cyclic saturated hydrocarbon base with 3-6 carbon atom with the straight or branched saturated hydrocarbyl of 1-6 carbon atom; Wherein one or more carbon atoms are optionally substituted with one or more halogen atoms;
Alkoxyl group is the straight or branched saturated hydrocarbyl with 1-6 carbon atom; Or for having the cyclic saturated hydrocarbon base of 3-6 carbon atom; Or for connecting the cyclic saturated hydrocarbon base with 3-6 carbon atom with the straight or branched saturated hydrocarbyl of 1-6 carbon atom; Wherein each carbon atom is optionally replaced by oxygen.
2. the compound of structure according to claim 1, is characterized in that:
Wherein R
1, R
2represent hydrogen, alkyl independently of one another;
Ar is selected from phenyl, and wherein phenyl can optionally by one or two R
3replace, R
3can be hydrogen, halogen, haloalkyl, alkoxyl group.
3. the compound of structure according to claim 1, is characterized in that:
Wherein R
1, R
2represent hydrogen, methyl independently of one another;
Ar is selected from phenyl, and wherein phenyl can optionally by one or two R
3replace, R
3can be hydrogen, chlorine, fluorine, trifluoromethyl, methoxyl group.
4. the compound of structure according to claim 1, it is characterized in that in following compound arbitrary:
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-benzamide (I-1);
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-4-chlorobenzamide (I-2);
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-4-fluorobenzamide (I-3);
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-4-methoxy benzamide (I-4);
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-4-trifluoromethyl benzamide (I-5);
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-2,6-dichloro-benzamides (I-6);
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-2,6-difluorobenzamides (I-7);
N-(3-(6-(2-5-methyl-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-2,6-dichloro-benzamides (I-8);
N-(3-(6-(2-6-methyl-7H-pyrrolo-[2,3-d] pyrimidyl) oxygen base) pyridyl)-2,6-dichloro-benzamides (I-9).
5., according to the preparation method of the arbitrary described structural compounds of Claims 1 to 4, it is characterized in that, preparation method is as follows:
Wherein R
1, R
2represent hydrogen, alkyl, cyano group, halogen, haloalkyl, hydroxyl, alkoxyl group independently of one another;
Ar is selected from phenyl, and wherein phenyl can optionally by one or more R
3replace, R
3can be hydrogen, alkyl, cyano group, halogen, haloalkyl, hydroxyl, alkoxyl group;
There is halogenating reaction and obtain Compound I-b in Compound I-a and 2-hydroxyl-5-nitropyridine, then through the reduction of palladium carbon, obtain Compound I further with the condensation of substituted aryl formic acid under alkali effect.
6. preparation method according to claim 5, is characterized in that, the alkali used when Compound I-a prepares Compound I-b is salt of wormwood, sodium carbonate, cesium carbonate, sodium methylate, sodium ethylate, potassium tert.-butoxide or sodium tert-butoxide.
7. preparation method according to claim 5, is characterized in that, the alkali used when Compound I-a prepares Compound I-b is cesium carbonate.
8. preparation method according to claim 5, is characterized in that, when Compound I-a prepares Compound I-b, temperature of reaction is 25-110 DEG C.
9. preparation method according to claim 5, is characterized in that, when Compound I-a prepares Compound I-b, temperature of reaction is 75 DEG C.
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| CN1918158A (en) * | 2004-02-14 | 2007-02-21 | Irm责任有限公司 | Compounds and compositions as protein kinase inhibitors |
| CN101594871A (en) * | 2006-05-26 | 2009-12-02 | 诺瓦提斯公司 | Pyrrolopyrimidine compounds and uses thereof |
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