CN108623582A - A kind of novel preparation method containing substituent pyridine and pyrimidine compound - Google Patents
A kind of novel preparation method containing substituent pyridine and pyrimidine compound Download PDFInfo
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- CN108623582A CN108623582A CN201710932669.8A CN201710932669A CN108623582A CN 108623582 A CN108623582 A CN 108623582A CN 201710932669 A CN201710932669 A CN 201710932669A CN 108623582 A CN108623582 A CN 108623582A
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- alkyl
- heteroaryl
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- VRJQXIWRSPPKML-UHFFFAOYSA-N Bc(cc1)ccc1S(Nc1c2nc(C)ccc2nc(Sc2n[n](C)cn2)n1)(=O)=O Chemical compound Bc(cc1)ccc1S(Nc1c2nc(C)ccc2nc(Sc2n[n](C)cn2)n1)(=O)=O VRJQXIWRSPPKML-UHFFFAOYSA-N 0.000 description 1
- CLTQBGIOANAKPZ-UHFFFAOYSA-N Cc(ccc1n2)nc1c(N)nc2Sc1n[n](C)cn1 Chemical compound Cc(ccc1n2)nc1c(N)nc2Sc1n[n](C)cn1 CLTQBGIOANAKPZ-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention belongs to field of medicine and chemical technology, specifically provide a kind of novel preparation method containing substituent pyridine and pyrimidine compound.Pyridopyrimidine compound has great importance on medical research and new drug development.The present invention solves the problems, such as to be easy to be destroyed under the high temperature conditions by highly basic in amides compound building-up process, 4 bit amino of pyrimidine is solved the problems, such as simultaneously since amino activity is poor it is difficult to reaction synthesizing amide, and it is that amide two-step reaction is completed in single step reaction that nitro, which is reduced to amino with cyan-hydrolysis, simplifies reaction process.The present invention provides the preparation method of this kind of compound, the application to such compound in the following new drug development field provides the important support of synthesis condition, method and technique etc..
Description
Technical field
The present invention relates to it is a kind of it is novel containing substituent pyridine and pyrimidine compound with and preparation method thereof research.
Background technology
Pyrido-pyrimidines are a kind of common nitrogen-containing hetero cyclics, are become with its potential bioactivity
One of hot spot of drug research.Pharmaceutical research shows：This kind of compound can be used in sterilization, anti-inflammatory, antitumor, gout, painstaking effort
There is good effect, which part compound to be also developed to for pipe disease, antiviral and phosphodiesterase inhibitors etc.
Commodity.Pyrido-pyrimidines are paid close attention to its antitumor and antibacterial activity by researcher especially, become drug
One important directions of research and development.
According to its design feature, pyrido-pyrimidines are broadly divided into three classes, pyrido [2,3-d] miazines chemical combination
Object, pyrido [1,2-a] pyrimidines, pyrido [4,3-d] pyrimidines.Wherein, pyrido [2,3-d] pyrimidine
Class compound is more in the report of Field of Drug Discovery, in the potentiality bigger of Field of Drug Discovery, we mainly study its with
And corresponding preparation method.
Invention content
It is novel containing substituent pyridine and pyrimidine compound that the invention mainly solves the technical problem of providing a kind of classes
Preparation method.
For achieving the above object, the application the present invention provides the compound of general formula in preparation method.
Formulas I
Wherein,
R1, R2, R3, R4, R5 be selected from aryl, heteroaryl, substituted heteroaryl, aryloxy, halogen, cyano, C1-6 alkyl,
C1-6 alkoxies, C1-6 alkoxy carbonyls；
R6 is selected from hydrogen or C1-6 alkyl；
R7 is selected from hydrogen, halogen, aryl, heteroaryl, substituted heteroaryl；
X is selected from sulphur, oxygen or nitrogen-atoms.
The term " alkyl " used in the present invention refers to the linear chain or branched chain monovalent hydrocarbon of saturation, has 1-8 carbon atom
(i.e. C1-8 alkyl), preferably 1-6 carbon atom (i.e. C1-6 alkyl), 1-4 carbon atoms (i.e. C1-4 alkyl) or 1-3 carbon atom
(i.e. C1-3 alkyl).The example of " alkyl " includes but not limited to methyl, ethyl, positive third class, isopropyl, normal-butyl, tertiary butyl, just
Amyl, neopentyl, n-hexyl, 2- methyl amyls, 2,2- dimethylbutyls, 3,3- dimethylbutyls etc..
Term used herein " halogen " refers to fluorine, chlorine, bromine or iodine, and preferred halogen group is fluorine, chlorine or bromine.
Term used herein " aryl " refers to that there are one the virtues of 5-14 carbon atom of monocycle or multiple fused rings for tool
Race's carbocylic radical.The aryl preferably has 5-10,5-8 or 5-6 or 6 carbon atom.The example of " aryl " includes but not limited to benzene
Base, naphthalene and anthryl etc..
Term used herein " heteroaryl " refers to the heteroaromatic rings group for having 5-14 member, including monocycle heteroaryl
Race and polycyclic aromatic ring, wherein monocyclic aromatic ring and other one or more aromatic rings are condensed.Heteroaryl has one or more
Choosing is independently from the ring hetero atom of N, O and S.Also included in term used herein " heteroaryl " range is wherein aromatic ring
The condensed group with one or more non-aromatic rings (carbocyclic ring or heterocycle), wherein linking group or point are located on aromatic ring." heteroaryl
Base " example includes but not limited to pyridyl group, pyrimidine radicals, imidazole radicals, pyrrole radicals, pyrazolyl, oxazolyl, thiazolyl, furyl, benzene
And imidazole radicals, benzothienyl, benzofuranyl, indyl, benzothiazolyl, benzoxazolyl, quinolyl etc..
The preparation method of above compound of the present invention, includes the following steps：
The preparation method of compound：Compound A and cuprous cyanide are in solvent N-methyl pyrilidone under 180 degrees Celsius
Reaction 0.5h obtains compound B.Compound B is reacted with iron powder under 50 degrees Celsius in tetrahydrofuran with saturated ammonium chloride solution
1h obtains compound C.Compound C reacts 3h under 105 degrees Celsius and obtains chemical combination in Isosorbide-5-Nitrae-dioxane solution with triphosgene
Object D.Compound D heated at reflux overnight in phosphorus oxychloride obtains compound E.Compound E in tetrahydrofuran solution with ammonia
It reacts to obtain compound F.Chemical combination is obtained by the reaction with triazole class compounds in n,N-Dimethylformamide solution in compound F
Object G.Target compound is obtained by the reaction with sulfonic acid chloride class compound in n,N-Dimethylformamide solution in compound G.
Wherein, X, R1, R2, R3, R4, R5, R6, R7 are as previously described.
The invention will be further described below.
All documents recited in the present invention, their full content are incorporated by reference into the present invention, and if these
Meaning expressed by document and when the inconsistent present invention, is subject to the statement of the present invention.In addition, the various terms that the present invention uses
With phrase have well known to a person skilled in the art general senses, nonetheless, the present invention is remained desirable at this to these terms
It is described in more detail and explains with phrase, the term and phrase referred to is if any inconsistent with common art-recognized meanings, with institute of the present invention
Subject to the meaning of statement.
In the method for present invention synthesis compound, the various raw material that react used are those skilled in the art according to
There is knowledge that can be prepared, or can be by made from method well known to document, or business can be passed through and purchased
.Intermediate, raw material, reagent, reaction condition etc. used in the above reaction scheme can be according to people in the art
Member existing knowledge, which can be made, suitably to be changed.
Specific implementation mode
Compound synthesis method is with the bromo- N- of compound 4- (the chloro- 2- of 6- ((1- methyl-1s H-1,2,4- triazoles) sulfydryl) pyrroles
Pyridine simultaneously [3,2-d] pyrimidine) for benzsulfamide：
1) preparation of the chloro- pyridines of 2- cyano -3- nitros 6-：
It takes 19.3g 2,6- dichloro-3-nitropyridines, 200ml N-Methyl pyrrolidones to make solvent, 17.9g cyanidings is added
It is cuprous, under nitrogen protection 0.5h is reacted under 180 degrees Celsius.Reaction finishes, and ethyl acetate 1500ml is added into reaction system,
Stir 30min, filtering, a small amount of ethyl acetate rinse of filter cake.The ethyl acetate solution of gained saturated common salt water washing 3 times,
Anhydrous sodium sulfate is dried, and concentration obtains crude product.The crude product petroleum ether of gained, ethyl acetate system are recrystallized, obtained
Pale solid, weigh 9.1g after dry.
2) preparation of 3- amino -6- chloropyridines -2- formamides：
The chloro- pyridines of 9.1g 2- cyano -3- nitros 6- are taken, 200ml THF, 100ml saturated ammonium chloride solutions, 16.8g is added
Iron powder reacts 1h under 50 degrees Celsius.Reaction finishes, and is cooled to room temperature, and filtering, filter cake ethyl acetate rinse obtains organic
Solution.The organic solution of gained washed once with saturated sodium bicarbonate solution, saturated salt solution respectively, and then anhydrous sodium sulfate is dry
It is dry, it is concentrated to give product, weigh 6.8g after dry.
3) preparation of 6- chloropyridines simultaneously [3,2-d] pyrimidine -2,4 (1H, 3H)-diketone：
6.8g 3- amino -6- chloropyridine -2- formamides are taken, Isosorbide-5-Nitrae-dioxane 220ml, triphosgene 4.7g is added, in
3h is reacted under 105 degrees Celsius.Reaction finishes, and is cooled to room temperature, and the water stirring 30min of 1ml, filtering is added, and filter cake is washed with EA
Once, dry, obtain product 6.2g.
4) 2, the preparation of 4,6- trichloropyridines simultaneously [3,2-d] pyrimidine：
6.2g 6- chloropyridines simultaneously [3,2-d] pyrimidine -2,4 (1H, 3H)-diketone is taken, the phosphorus oxychloride of 60ml is added, 115 take the photograph
Heated overnight at reflux under family name's degree.Reaction finishes, and a large amount of phosphorus oxychloride are removed under reduced pressure, and ethyl acetate 200ml is added, and stirs 10min.
Saturated sodium bicarbonate solution 300ml is slowly added into system again, stirs 30min.By mixed system liquid separation, organic phase is used respectively
Saturated sodium bicarbonate, saturated salt solution washed once, and then anhydrous sodium sulfate is dried, and concentration obtains crude product.By the thick of gained
Product crosses column (silicagel column), isolated 3.4g white products.
5) preparation of 2,6-, bis- chloro- 4-aminopyridines simultaneously [3,2-d] pyrimidine：
2,4,6- trichloropyridines of 1.17g simultaneously [3,2-d] pyrimidine is taken, tetrahydrofuran 20ml is added, is stirred under 0 degree Celsius
10min, then into reaction system be added 1ml saturation ammonia spirit, react 2h at room temperature, TLC shows that the reaction was complete.It has reacted
Finish, be removed under reduced pressure THF, 10ml water is added, is filtered after stirring 10min, after filter cake a small amount of water flushing, dry off-white powder
Product 1.03g.
6) preparation of 2- ((1- methyl-1s H-1,2,4- triazoles) sulfydryl) the chloro- pyridos of -4- amino -6- [3,2-d] pyrimidine：
Take 0.69g 4- methyl -4H-3- sulfydryls -1,2,4- triazoles that the dissolving of 10ml N-Methyl pyrrolidones, 0.24g is added
Sodium hydrogen, reacts 0.5h at room temperature.2,6-, bis- chloro- 4-aminopyridines simultaneously [3,2-d] pyrimidine is added into reaction system again, in
10h is reacted under 120 degrees Celsius.Reaction finishes, and solvent N-methyl pyrilidone is removed under reduced pressure, and water 5ml is added, after stirring 10min
Filtering, dry crude product after filter cake a small amount of water flushing.The crude product of gained filters after being beaten with 30ml dichloromethane, dry
Product 1.1g is obtained afterwards.
7) (the chloro- 2- of 6- ((1- methyl-1s H-1,2,4- triazoles) sulfydryl) pyrido [3,2-d] is phonetic by the bromo- N- of compound 4-
Pyridine) benzsulfamide preparation：
0.4g 2- ((1- methyl-1s H-1,2,4- triazoles) sulfydryl) the chloro- pyridos of -4- amino -6- [3,2-d] pyrimidine is taken,
DMF10ml is added, stirs 10min under 0 degree Celsius, then 0.1g sodium hydrogen is added into reaction system, the reaction was continued 15min.Again
0.42g p-bromobenzenesulfonyl chlorides are added into reaction system, reaction at room temperature is stayed overnight.Reaction finishes, and DMF is removed under reduced pressure, and water is added
8ml, stirring 10min has white solid precipitation with the hydrochloric acid solution tune pH value of 1mol/l to 5 or so, after continuing stirring 30 minutes
Filtering, dry the bromo- N- of compound 4- (the chloro- 2- of 6- ((1- methyl-1s H-1,2,4- triazoles) mercaptos after filter cake a small amount of water flushing
Base) pyrido [3,2-d] pyrimidine) benzsulfamide 0.3g.1H-NMR(6d-DMSO)：δ 8.91 (s, 1H), 8.01-7.98 (m, 1H),
7.98-7.96 (m, 2H), 7.83-7.80 (m, 2H), 7.31-7.28 (m, 1H), 3.67 (s, 3H).
Claims (2)
1. the present invention provides application of the compound of general formula in preparation method.
Formulas I
Wherein,
R1, R2, R3, R4, R5 are selected from aryl, heteroaryl, substituted heteroaryl, aryloxy, halogen, cyano, C1-6 alkyl, C1-6
Alkoxy, C1-6 alkoxy carbonyls；
R6 is selected from hydrogen or C1-6 alkyl；
R7 is selected from hydrogen, halogen, aryl, heteroaryl, substituted heteroaryl；
X is selected from sulphur, oxygen or nitrogen-atoms.
The term " alkyl " used in the present invention refers to the linear chain or branched chain monovalent hydrocarbon of saturation, has 1-8 carbon atom (i.e.
C1-8 alkyl), preferably 1-6 carbon atom (i.e. C1-6 alkyl), 1-4 carbon atoms (i.e. C1-4 alkyl) or 1-3 carbon atom is (i.e.
C1-3 alkyl).The example of " alkyl " includes but not limited to methyl, ethyl, positive third class, isopropyl, normal-butyl, tertiary butyl, positive penta
Base, neopentyl, n-hexyl, 2- methyl amyls, 2,2- dimethylbutyls, 3,3- dimethylbutyls etc..
Term used herein " halogen " refers to fluorine, chlorine, bromine or iodine, and preferred halogen group is fluorine, chlorine or bromine.
Term used herein " aryl " refers to that there are one the aromatic carbons of 5-14 carbon atom of monocycle or multiple fused rings for tool
Ring group.The aryl preferably has 5-10,5-8 or 5-6 or 6 carbon atom.The example of " aryl " includes but not limited to phenyl, naphthalene
Base and anthryl etc..
Term used herein " heteroaryl " refers to the heteroaromatic rings group for having 5-14 member, including Monocyclic heteroaromatic and
Polycyclic aromatic ring, wherein monocyclic aromatic ring and other one or more aromatic rings are condensed.Heteroaryl has one or more choosings only
On the spot from the ring hetero atom of N, O and S.Also included in term used herein " heteroaryl " range is wherein aromatic ring and one
The condensed group of a or multiple non-aromatic rings (carbocyclic ring or heterocycle), wherein linking group or point are located on aromatic ring." heteroaryl "
Example includes but not limited to pyridyl group, pyrimidine radicals, imidazole radicals, pyrrole radicals, pyrazolyl, oxazolyl, thiazolyl, furyl, benzo
Imidazole radicals, benzothienyl, benzofuranyl, indyl, benzothiazolyl, benzoxazolyl, quinolyl etc..
2. the preparation method of the compound described in claim 1, includes the following steps：
The preparation method of compound：Compound A and cuprous cyanide react in solvent N-methyl pyrilidone under 180 degrees Celsius
0.5h obtains compound B.Compound B tetrahydrofuran with react 1h under 50 degrees Celsius with iron powder in saturated ammonium chloride solution and obtain
To compound C.Compound C reacts 3h under 105 degrees Celsius and obtains compound D in Isosorbide-5-Nitrae-dioxane solution with triphosgene.
Compound D heated at reflux overnight in phosphorus oxychloride obtains compound E.Compound E occurs in tetrahydrofuran solution with ammonia
Compound F is obtained by the reaction.Compound G is obtained by the reaction in compound F in n,N-Dimethylformamide solution with triazole class compounds.
Target compound is obtained by the reaction with sulfonic acid chloride class compound in n,N-Dimethylformamide solution in compound G.
Wherein, X, R1, R2, R3, R4, R5, R6, R7 are as previously described.
The invention will be further described below.
All documents recited in the present invention, their full content are incorporated by reference into the present invention, and if these documents
Expressed meaning and when the inconsistent present invention, is subject to the statement of the present invention.In addition, various terms that the present invention uses and short
Language has that well known to a person skilled in the art general senses, and nonetheless, the present invention is remained desirable at this to these terms and short
Language is described in more detail and explains, the term and phrase referred to is stated with the present invention if any inconsistent with common art-recognized meanings
Meaning subject to.
In the method for present invention synthesis compound, the various raw material for reacting used are that those skilled in the art know according to existing
Knowing can be prepared, or can be by made from method well known to document, or can by commercially available.
Intermediate, raw material, reagent, reaction condition etc. used in the above reaction scheme can have according to those skilled in the art
Knowledge, which can be made, suitably to be changed.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060199803A1 (en) * | 2005-02-25 | 2006-09-07 | Kudos Pharmaceuticals Ltd | Compounds |
| EP1831217A2 (en) * | 2004-12-30 | 2007-09-12 | 4 Aza Ip Nv | Pyrido(3,2-d)pyrimidines and pharmaceutical compositions useful for medical treatment |
| CN105283454A (en) * | 2013-04-12 | 2016-01-27 | 阿萨纳生物科技有限责任公司 | Quinazolines and azaquinazolines as dual inhibitors of RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/MTOR pathways |
| CN106668008A (en) * | 2015-11-10 | 2017-05-17 | 河南省锐达医药科技有限公司 | Target anti-cancer medicine based on STAT3 (Signal Transducers and Activators of Transcription type 3) protein target spot |
-
2017
- 2017-10-10 CN CN201710932669.8A patent/CN108623582A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1831217A2 (en) * | 2004-12-30 | 2007-09-12 | 4 Aza Ip Nv | Pyrido(3,2-d)pyrimidines and pharmaceutical compositions useful for medical treatment |
| US20060199803A1 (en) * | 2005-02-25 | 2006-09-07 | Kudos Pharmaceuticals Ltd | Compounds |
| CN101128204A (en) * | 2005-02-25 | 2008-02-20 | 库多斯药物有限公司 | 2,4-diamino-pyridopyrimidine derivatives and their use as mTOR inhibitors |
| CN105283454A (en) * | 2013-04-12 | 2016-01-27 | 阿萨纳生物科技有限责任公司 | Quinazolines and azaquinazolines as dual inhibitors of RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/MTOR pathways |
| CN106668008A (en) * | 2015-11-10 | 2017-05-17 | 河南省锐达医药科技有限公司 | Target anti-cancer medicine based on STAT3 (Signal Transducers and Activators of Transcription type 3) protein target spot |
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