CN106810550A - A kind of preparation method of 7-naphthyridine derivatives - Google Patents
A kind of preparation method of 7-naphthyridine derivatives Download PDFInfo
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- CN106810550A CN106810550A CN201710017410.0A CN201710017410A CN106810550A CN 106810550 A CN106810550 A CN 106810550A CN 201710017410 A CN201710017410 A CN 201710017410A CN 106810550 A CN106810550 A CN 106810550A
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- Prior art keywords
- trifluoromethyl
- reaction
- naphthyridines
- solvent
- chloro
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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 discloses a kind of (trifluoromethyl) 1 of 5 chlorine of 7-naphthyridine derivatives 3, the preparation method of 8 naphthyridines, it is initiation material with the amine of (trifluoromethyl) pyridine 2, (trifluoromethyl) 1 of 5 chlorine 3 is obtained by cyclization, chlorination, reduction, 8 naphthyridines, the compound is the important intermediate of new drug development.
Description
Technical field
The present invention relates to a kind of preparation method of important medicine intermediate, the chloro- 3- (fluoroforms of more particularly to compound 5-
Base) -1,8- naphthyridines and its synthetic method.
Technical background
The chloro- 3- of compound 5- (trifluoromethyl) -1,8- naphthyridines, structural formula is：
The compound is the important intermediate for synthesizing naphthyridines analog derivative.7-naphthyridine derivatives are by consuming the protein of ATP
The suppression of the signal transduction carried out such as kinases, adjust and/or regulate and control its effect.Change with reference to ATP and using its energy conformation,
Make the protein of substrate phosphorylation and enabling signal Cascaded amplification known from many types, such as kinases, phosphatase, chaperone
Or isomerase.ATP- associated proteins can be enriched with using specific instrument and technology.As the mechanism part of cancer markers,
Ser/Thr kinases and receptor tyrosine kinase are required phosphorylases in cellular signal transduction.Cell cycle, survival, increment
The cell processes that are adjusted by cellular signal transduction with cell death, with allow tissue growth, regeneration and in homeostasis or
Degenerate.Therefore, some kinases are the sensitive targets of mammalian therapeutic.In swashing for the different parts as human kinase group
In enzyme system row, receptor tyrosine KDR can be survived and be bred with stimulating endothelial cell, and condition is by the extracellular connections of VEGF.Then, match somebody with somebody
Body combination can cause intracellular phosphorylation event, i.e. signal cascade to amplify, and ultimately result in propagation.
At present, other patent literatures compound and its synthetic method be there are no.
The content of the invention
The invention discloses a kind of synthetic method of the chloro- 3- of 5- (trifluoromethyl) -1,8- naphthyridines, with (trifluoromethyl) pyrrole
Pyridine -2- amine is initiation material, and the chloro- 3- of 5- (trifluoromethyl) -1,8- naphthyridines is obtained by cyclization, chlorination, reduction three-step reaction, should
Compound is the important intermediate for synthesizing 7-naphthyridine derivatives.Synthesis step is as follows：
(1) it is initiation material with (trifluoromethyl) pyridine -2- amine, 2 is obtained with diethyl malonate reaction,
(2) 2 and chlorination reaction, 3 are obtained；
(3) reduced 3, obtained 4
One preferred embodiment in, described synthesis compound (trifluoromethyl) -1,8- naphthyridines -2,4- glycol it is anti-
Cyclization reagent that should be used is selected from diethyl malonate；Chlorinating agent used by described chlorination reaction synthesis compound 3 is selected from three
Chlorethoxyfos；Reducing agent used by described reduction reaction synthesis 5- chloro- 3- (trifluoromethyl) -1,8- naphthyridines is selected from Pd/C- hydrogen.
In another preferred embodiment, it is characterised in that described synthesis compound (trifluoromethyl) -1,8- naphthalenes
The reaction solvent for use of pyridine -2,4- glycol is selected from tetrahydrofuran；Solvent used by described chlorination reaction synthesis compound 3 is selected from
POCl3；Solvent used by described reduction reaction synthesis 5- chloro- 3- (trifluoromethyl) -1,8- naphthyridines is selected from methyl alcohol.
In further preferred embodiment, it is characterised in that described synthesis compound (trifluoromethyl) -1,8- naphthalenes
The reaction temperature of pyridine -2,4- glycol is the reflux temperature of solvent；Reaction temperature used by described chlorination reaction synthesis compound 3
It is the reflux temperature of solvent；The reaction temperature of described reduction reaction synthesis 5- chloro- 3- (trifluoromethyl) -1,8- naphthyridines is room
Temperature.
The present invention relates to the chloro- 3- of 5- (trifluoromethyl) -1,8- naphthyridines and its synthetic method, the compound is synthesis synthesis naphthalene
The important intermediate of piperidine derivatives, currently without other Patents documents report.
The present invention is further described by the following embodiment, and these descriptions are not present invention to be made into one
The restriction of step.It should be understood by those skilled in the art that the equivalent made to technical characteristic of the invention, or change accordingly
Enter, still fall within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of (trifluoromethyl) -1,8- naphthyridines -2,4- glycol
(trifluoromethyl) pyridine -2- amine, 24ml diethyl malonates 30g are added in 160ml tetrahydrofurans, are stirred
Mix, heat, flow back 4 hours, cooling is concentrated under reduced pressure, the residue isolated 37g products of chromatographic column.
(2) synthesis of 2,4- bis- chloro- 6- (trifluoromethyl) -1,8- naphthyridines
First step products therefrom 35g is dissolved in 200ml POCl3s, is heated to reflux, reacted 12 hours, reaction solution is poured into
In frozen water, it is extracted with ethyl acetate, organic phase is washed three times with saturated common salt, then with anhydrous sodium sulfate drying, is concentrated under reduced pressure, remains
The excess isolated product 18g grease of chromatographic column.
(3) synthesis of the chloro- 3- of 5- (trifluoromethyl) -1,8- naphthyridines
15g 1,8- benzodiazine -2,4- dichloros are added in 200ml methyl alcohol, 3g 10%Pd/C are added, hydrogen is passed through
Filtrate, concentration, the residue isolated product 7.8g of chromatographic column are collected in gas, room temperature reaction 2 hours, filtering.
Claims (6)
1. the method that one kind prepares the chloro- 3- of 5- (trifluoromethyl) -1,8- naphthyridines, with (trifluoromethyl) pyridine -2- amine as initial former
Material, the chloro- 3- of 5- (trifluoromethyl) -1,8- naphthyridines is obtained by cyclization, chlorination, reduction three-step reaction, and synthetic route is as follows,
2. method according to claim 1, it is characterized by described 3 steps reaction is,
(1) it is initiation material with (trifluoromethyl) pyridine -2- amine, 2 is obtained with diethyl malonate reaction,
(2) 2 and chlorination reaction, 3 are obtained；
(3) reduced 3, obtained 4
3. method according to claim 1, it is characterised in that described synthesis compound (trifluoromethyl) -1,8- naphthyridines -2,4-
Cyclization reagent used by the reaction of glycol is selected from one or two the mixture in diethyl malonate or dimethyl malenate；
Chlorinating agent used by described chlorination reaction synthesis compound 3 is selected from hydrogen chloride, phosphorus trichloride, phosphorus pentachloride, POCl3
The mixture of one or more；Reducing agent used by described reduction reaction synthesis 5- chloro- 3- (trifluoromethyl) -1,8- naphthyridines
Selected from the mixing of one or more in Pd/C- hydrogen, palladium dydroxide/C- hydrogen, iron powder, zinc powder, sodium borohydride, potassium borohydride
Thing.
4. method according to claim 1, it is characterised in that described synthesis compound (trifluoromethyl) -1,8- naphthyridines -2,4-
The reaction solvent for use of glycol is selected from tetrahydrofuran, N,N-dimethylformamide, toluene, methyl alcohol, ethanol, normal propyl alcohol, isopropanol
In the mixture of one or more；Solvent used by described chlorination reaction synthesis compound 3 is selected from tetrahydrofuran, dichloromethane
The mixture of one or more in alkane, chloroform, carbon tetrachloride, thionyl chloride, POCl3；Described reduction reaction synthesis 5-
Solvent used by chloro- 3- (trifluoromethyl) -1,8- naphthyridines is selected from one or more in methyl alcohol, ethanol, normal propyl alcohol, isopropanol
Mixture.
5. method according to claim 1, it is characterised in that described synthesis compound (trifluoromethyl) -1,8- naphthyridines -2,4-
The reaction temperature of glycol is the reflux temperature of 0 DEG C-solvent；Reaction temperature used by described chlorination reaction synthesis compound 3 is 0
DEG C-reflux temperature of solvent；The reaction temperature of described reduction reaction synthesis 5- chloro- 3- (trifluoromethyl) -1,8- naphthyridines is 0
DEG C-reflux temperature of solvent.
6. method according to claim 1, it is characterised in that described synthesis compound (trifluoromethyl) -1,8- naphthyridines -2,4-
The reaction temperature of glycol is the reflux temperature of solvent；Reaction temperature used by described chlorination reaction synthesis compound 3 is solvent
Reflux temperature；The reaction temperature of described reduction reaction synthesis 5- chloro- 3- (trifluoromethyl) -1,8- naphthyridines is room temperature.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201710017410.0A CN106810550A (en) | 2017-01-10 | 2017-01-10 | A kind of preparation method of 7-naphthyridine derivatives |
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| CN201710017410.0A CN106810550A (en) | 2017-01-10 | 2017-01-10 | A kind of preparation method of 7-naphthyridine derivatives |
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| CN201710017410.0A Pending CN106810550A (en) | 2017-01-10 | 2017-01-10 | A kind of preparation method of 7-naphthyridine derivatives |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113620946A (en) * | 2021-09-03 | 2021-11-09 | 山东明化新材料有限公司 | Preparation method of 2-chloro-1, 8-naphthyridine derivatives |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1802379A (en) * | 2003-06-04 | 2006-07-12 | 拜尔农作物科学股份公司 | Triazolopyrimidines |
| CN1839136A (en) * | 2003-06-27 | 2006-09-27 | 拜尔农作物科学股份公司 | Pyrazolopyrimidines |
| CN101754681A (en) * | 2007-06-08 | 2010-06-23 | 海利空医疗公司 | Therapeutic pyrazolonaphthyridinderivatives derivatives |
| CN102958930A (en) * | 2010-06-28 | 2013-03-06 | 默克专利有限公司 | 2,4- diaryl - substituted [1,8] naphthyridines as kinase inhibitors for use against cancer |
| CN104086543A (en) * | 2014-06-19 | 2014-10-08 | 湖南华腾制药有限公司 | Method for preparing 4-chloro-1,8-naphthyridine |
-
2017
- 2017-01-10 CN CN201710017410.0A patent/CN106810550A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1802379A (en) * | 2003-06-04 | 2006-07-12 | 拜尔农作物科学股份公司 | Triazolopyrimidines |
| CN1839136A (en) * | 2003-06-27 | 2006-09-27 | 拜尔农作物科学股份公司 | Pyrazolopyrimidines |
| CN101754681A (en) * | 2007-06-08 | 2010-06-23 | 海利空医疗公司 | Therapeutic pyrazolonaphthyridinderivatives derivatives |
| CN102958930A (en) * | 2010-06-28 | 2013-03-06 | 默克专利有限公司 | 2,4- diaryl - substituted [1,8] naphthyridines as kinase inhibitors for use against cancer |
| CN104086543A (en) * | 2014-06-19 | 2014-10-08 | 湖南华腾制药有限公司 | Method for preparing 4-chloro-1,8-naphthyridine |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113620946A (en) * | 2021-09-03 | 2021-11-09 | 山东明化新材料有限公司 | Preparation method of 2-chloro-1, 8-naphthyridine derivatives |
| CN113620946B (en) * | 2021-09-03 | 2022-06-21 | 山东明化新材料有限公司 | Preparation method of 2-chloro-1, 8-naphthyridine derivatives |
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