CN108440522A - A kind of bis- chloro- 1H- imidazos [4,5-C] pyridines -2 of 4,6-（3H）The synthetic method of -one - Google Patents
A kind of bis- chloro- 1H- imidazos [4,5-C] pyridines -2 of 4,6-（3H）The synthetic method of -one Download PDFInfo
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- CN108440522A CN108440522A CN201810362760.5A CN201810362760A CN108440522A CN 108440522 A CN108440522 A CN 108440522A CN 201810362760 A CN201810362760 A CN 201810362760A CN 108440522 A CN108440522 A CN 108440522A
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- 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 one kind 4,6 dichloro 1H imidazos [4,5 C] pyridine 2 (3H) ketone synthetic method, with 2,6 dichloro, 3 amino, 4 pyridine carboxylic acid methyl esters be predominant starting material, it is passed through ammonia in a solvent, ammonolysis reaction occurs, can be obtained by compound 2 by simple process, then direct Hoffmann rearrangement and cyclization, under suitable conditions, target compound 3 is obtained.The relatively existing route steps of this route are shorter, and entire route is substantially unit process, and target compound just can be obtained through simple process in easy to operate, mild condition, and whole route yield is higher；Prodigious economic benefit and social benefit will be brought by carrying out production with the route.In brief, synthetic method of the invention has the characteristics that：Reaction condition is mild, and technological operation is simple, environmentally protective, at low cost, high income.
Description
Technical field
The present invention relates to a kind of synthetic methods of bis- chloro- 1H- imidazos [4,5-C] pyridine -2 (3H) -one of 4,6-.
Background technology
4,6- bis- chloro- 1H- imidazos [4,5-C] pyridine -2 (3H) -one are to treat or prevent to be related to by CGRP (calcitonins
Gene related peptide) headache caused by receptor antagonist variation, the important intermediate of the new drug of migraine and cluster headache, CAS
Number be [668268-68-6], molecular formula is as follows:
The compound is had a headache for caused by CGRP (calcitonin gene-related peptide) receptor antagonists changes of contents,
Migraine and cluster headache disease carry out treating a kind of drug, and such compound is acyl in single (or more) ring anilide loop coil
Amine Cgrp receptor antagonist.
4,6- bis- chloro- 1H- imidazos [4,5-C] pyridine -2 (3H) -one, are the important intermediates of the kind new medicine.Document report
Leading bis- chloro- 1H- imidazos [4,5-C] pyridine -2 (3H) -one synthetic methods of 4,6- mainly has two kinds:First, bis- chloro- 4- ammonia of 2,6-
Yl pyridines method, second is that 2,6- bis- chloro- 3,4- diamino-pyridines methods.
2,6- bis- chloro- 4-aminopyridine methods be with 2,6-, bis- chloro- 4-aminopyridines be raw material, through nitrification, reduction and cyclization
3 steps synthesize bis- chloro- 1H- imidazos [4,5-C] pyridine -2 (3H) -one of 4,6-.This method process route is long, and total recovery is general.This
Technique, for starting material, is carried out nitration reaction under the conditions of the concentrated sulfuric acid with concentrated nitric acid and obtained with 2,6-, bis- chloro- 4-aminopyridine methods
Product b, then reduction reaction obtain compound c.Compound c obtains product 3 with urea cyclization：Bis- chloro- 1H- imidazos of 4,6- [4,
5-C] pyridine -2 (3H) -one.Route such as following formula：
2,6- bis- chloro- 3,4- diamino-pyridines methods are that (above formula compound c) is with 2,6-, bis- chloro- 3,4- diamino-pyridines
Raw material synthesizes 4,6-, bis- chloro- 1H- imidazos [4,5-C] pyridine -2 (3H) -one through cyclization.This method process route is short, total to receive
Rate is fine.For this technique with 2,6-, bis- chloro- 3,4- diamino-pyridines for starting material, compound c obtains product with phosgene cyclization：
Bis- chloro- 1H- imidazos [4,5-C] pyridine -2 (3H) -one of 4,6-.Route is consistent with above formula final step.
The various method surveys for preparing bis- chloro- 1H- imidazos [4,5-C] pyridine -2 (3H) -one of 4,6- are as follows：
1.Nucleosides, Nucleotides and Nucleic Acid (22 (12), 2133-2144；2002) it reports
It, for starting material, is reacted through 3 steps and 4,6-, bis- chloro- 1H- imidazos [4,5-C] is made with 2,6-, bis- chloro- 4-aminopyridine methods in road
Pyridine -2 (3H) -one, reaction are nitrified using the concentrated sulfuric acid and concentrated nitric acid, have in addition used iron powder reducing, finally closed with urea
Ring.
2.WO20070061692 is reported with 2,6-, bis- chloro- 3,4- diamino-pyridines as starting material, is reacted and is made through 1 step
4,6-, bis- chloro- 1H- imidazos [4,5-C] pyridine -2 (3H) -one is obtained, reaction prepares product using phosgene ring-closure reaction.
The preparation method for summarizing 4,6-, bis- chloro- 1H- imidazos [4,5-C] pyridine -2 (3H) -one, predominantly with 2,6- bis-
Chloro- 4-aminopyridine is that raw material prepares bis- chloro- 1H- imidazos [4,5-C] pyridines -2 (3H)-of 4,6- using condensation ring-closure reaction
Ketone.This synthetic reaction route is nitrifying and sulfuric acid, nitric acid is largely used to generate a large amount of waste water in rearrangement reaction；In addition it restores
Reaction uses original iron powder reducing, produces a large amount of iron cement waste residue.An other route 2, bis- chloro- 3,4- diamino of 6-
Pyridine is starting material, and cost of material is very high, while being used to the prodigious phosgene cyclization of environmental disruption, also improper.Therefore existing
Some synthetic methods all there are various defects either reagent is not environmentally or yield is relatively low or spent acid and useless
Slag is too many, leads to cost costly.Existing technology path is being required for improving in terms of environment friendly and cost.
Invention content
The present invention is directed to problems of the prior art, provides a kind of easy to operate, at low cost, environmental-friendly, yield
The synthetic route of high bis- chloro- 1H- imidazos [4,5-C] pyridine -2 (3H) -one of 4,6-.
The present invention in order to achieve the above objectives, is realized by following technical proposals：
The invention discloses the synthetic method of 4,6- of one kind, bis- chloro- 1H- imidazos [4,5-C] pyridine -2 (3H) -one, with
2,6- bis- chloro- 3- amino-Isonicotinic acid methyl esters are predominant starting material, and mesh is obtained by ammonolysis and Hoffmann rearrangement reaction
Compound is marked, chemical equation is as follows：
Preparation process is as follows：
1) ammonolysis solution is added in compound 1, terminates through monitoring reaction, conventional treatment obtains compound 2；
2) compound 2 carries out Hoffmann rearrangement reaction under alkali effect, then heats automatic cyclization and generates compound 3.
As a further improvement, in step 1) of the present invention, the solvent of addition is methanol, ethyl alcohol, tetrahydrochysene furan
It mutters, any one in toluene, water, ammonolysis reaction temperature is 0-50 DEG C.
As a further improvement, in step 1) of the present invention, the solvent of addition is ethyl alcohol, then passes to ammonia
Ammonolysis；Ammonolysis reaction temperature is 15-30 DEG C.
As a further improvement, in step 2) of the present invention alkali be ethylenediamine, triethylamine, isopropylamine, DBU (1,
11 carbon -7- alkene of 8- diazabicylos), LDA (lithium diisopropylamine), butyl lithium, lithium hexamethyldisilazide, sodium hydrogen
In any one, reaction temperature be -10-50 DEG C.
As a further improvement, in step 2) of the present invention alkali be LDA or lithium hexamethyldisilazide, instead
It is 0-20 DEG C to answer temperature.
As a further improvement, in step 2) of the present invention, compound 2 under alkaline condition, carries out Huffman
Rearrangement reaction heats cyclization and obtains compound 3 after rearrangement；In above-mentioned reaction, reagent is sodium hypochlorite, in sodium hypobromite
Any one；Be temperature it is 50-100 DEG C resetting the reaction in cyclization stage.
Beneficial effects of the present invention are as follows：
The synthetic method of the present invention is with 2,6-, bis- chloro- 3- amino-Isonicotinic acid methyl esters for predominant starting material,
It is passed through ammonia in solvent, ammonolysis reaction occurs, can be obtained by compound 2 by simple process, then direct Hoffmann rearrangement
And cyclization obtains target compound 3 under suitable conditions.Relative to original technique, this route does not use sulphur largely
Acid and nitric acid, avoid one of the hazardous reaction in iodine：Nitration reaction；In addition this route does not use phosgene etc. pair
The prodigious reagent of environmental disruption participates in reaction；This route is cheap using starting material relative value simultaneously, and life is reduced from source
Produce cost.The relatively existing route steps of this route are shorter, and entire route is substantially unit process, easy to operate, condition temperature
With target compound just can be obtained through simple process, whole route yield is higher；Carrying out production with the route will bring
Prodigious economic benefit and social benefit.In brief, synthetic method of the invention has the characteristics that：Reaction condition is mild,
Technological operation is simple, environmentally protective, at low cost, high income.
Specific implementation mode
The present invention is described in further detail with reference to embodiment, but the scope of the invention is not limited to implement
Example.
Embodiment 1
1) equipped with mechanical agitation, reflux condensing tube, thermometer four-hole boiling flask in, by 20 g of compound 1 put into 30 grams
In ethyl alcohol, stirring is passed through ammonia and is warming up to 25 DEG C to complete molten, until 25-30 DEG C of heat preservation is for 24 hours, it, will be organic after monitoring ammonolysis is complete
Solvent recovery, residue cooling, is filtered, washed, dries, and obtains compound 2 and amounts to 17.71 grams, in terms of compound 1, yield is
95%.
2) equipped with mechanical agitation, reflux condensing tube, thermometer four-hole boiling flask in, by 20 g of compound 2 put into tetrahydrochysene
In furans, stirring is added the LDA of equivalent, after being stirred 30 minutes at 0 DEG C, (11%) 25 gram of fresh sodium hypochlorite is added dropwise, and drips
After the completion of adding, insulated and stirred 2 hours.After reaction, 70 DEG C are warming up to, 3h is kept the temperature at 70-75 DEG C, after the reaction was complete, drop
Temperature recycles organic solvent.After recycling, part water is added, is then extracted with ethyl acetate, organic layer is washed off with brine, dense
Contracting is dry, obtains compound 3 and amounts to 17.83 grams, in terms of compound 2, yield 90%.
Embodiment 2
1) equipped with mechanical agitation, reflux condensing tube, thermometer four-hole boiling flask in, by 20 g of compound 1 put into 30 grams
In toluene, stirring is passed through ammonia and is warming up to 10 DEG C, heat preservation for 24 hours, will be organic molten after monitoring ammonolysis is complete at 0-15 DEG C to complete molten
Agent is recycled, and residue cooling is filtered, washed, dries, and obtains compound 2 and amounts to 16.78 grams, in terms of compound 1, yield is
90%.
2) equipped with mechanical agitation, reflux condensing tube, thermometer four-hole boiling flask in, by 20 g of compound 2 put into tetrahydrochysene
In furans, it is added with stirring the lithium hexamethyldisilazide of equivalent and fresh hypochlorous acid is added dropwise after 20 DEG C are stirred 30 minutes
(11%) 25 gram of sodium, after being added dropwise to complete, insulated and stirred 2 hours.After reaction, 70 DEG C are warming up to, 3h is kept the temperature at 70-75 DEG C,
After the reaction was complete, organic solvent is recycled in cooling.After recycling, part water is added, is then extracted with ethyl acetate, organic layer
It is washed off with brine, concentration is dry, obtains compound 3 and amounts to 17.42 grams, in terms of compound 2, yield 88%.
Embodiment 3
1) equipped with mechanical agitation, reflux condensing tube, thermometer four-hole boiling flask in, by 20 g of compound 1 put into 30 grams
In methanol, stirring is passed through ammonia and is warming up to 10 DEG C to complete molten, until 10-25 DEG C of heat preservation is for 24 hours, it, will be organic after monitoring ammonolysis is complete
Solvent recovery, residue cooling, is filtered, washed, dries, and obtains compound 2 and amounts to 17.12 grams, in terms of compound 1, yield is
91.8%.
2) equipped with mechanical agitation, reflux condensing tube, thermometer four-hole boiling flask in, by 20 g of compound 2 put into tetrahydrochysene
In furans, stirring is added the butyl lithium of equivalent and fresh sodium hypobromite (11%) 30 is added dropwise after being stirred 30 minutes at -10 DEG C
Gram, after being added dropwise to complete, insulated and stirred 2 hours.After reaction, 50 DEG C are warming up to, 3h is kept the temperature at 50-55 DEG C, the reaction was complete
Afterwards, cool down, recycle organic solvent.After recycling, part water is added, is then extracted with ethyl acetate, organic layer is washed with salt
Fall, concentration is dry, obtains compound 3 and amounts to 17.03 grams, in terms of compound 2, yield 86%.
Embodiment 4
1) equipped with mechanical agitation, reflux condensing tube, thermometer four-hole boiling flask in, by 20 g of compound 1 put into 30 grams
In tetrahydrofuran, stirring is passed through ammonia and is warming up to 45 DEG C, heat preservation for 24 hours, will after monitoring ammonolysis is complete at 45-50 DEG C to complete molten
Organic solvent recycles, and residue cooling is filtered, washed, dries, and obtains compound 2 and amounts to 16.96 grams, in terms of compound 1, receives
Rate is 91%.
2) equipped with mechanical agitation, reflux condensing tube, thermometer four-hole boiling flask in, by 20 g of compound 2 put into tetrahydrochysene
It in furans, stirs, the DBU (1,8- diazabicylo, 11 carbon -7- alkene) of equivalent is added at 50 DEG C, after stirring 30 minutes, drop
Add (11%) 30 gram of fresh sodium hypobromite, after being added dropwise to complete, insulated and stirred 2 hours.After reaction, 100 DEG C are warming up to,
100 DEG C of heat preservation 3h, after the reaction was complete, organic solvent is recycled in cooling.After recycling, part water is added, then uses acetic acid second
Ester extracts, and organic layer is washed off with brine, and concentration is dry, obtains compound 3 and amounts to 17.23 grams, in terms of compound 2, yield is
86%.
Listed above is only the several specific embodiments of the present invention.It is clear that the invention is not restricted to which above example, may be used also
With there are many deformation, those skilled in the art directly can export or associate from present disclosure and is all
Deformation, is considered as protection scope of the present invention.
Claims (6)
1. one kind 4, the synthetic method of bis- chloro- 1H- imidazos [4,5-C] pyridine -2 (3H) -one of 6-, which is characterized in that with 2,6-
Two chloro- 3- amino-Isonicotinic acid methyl esters are predominant starting material, and target chemical combination is obtained by ammonolysis and Hoffmann rearrangement reaction
Object, chemical equation are as follows：
Preparation process is as follows：
1) ammonolysis solution is added in compound 1, terminates through monitoring reaction, conventional treatment obtains compound 2；
2) compound 2 carries out Hoffmann rearrangement reaction under alkali effect, then heats automatic cyclization and generates compound 3.
2. the synthetic method of 4,6-, bis- chloro- 1H- imidazos [4,5-C] pyridine -2 (3H) -one according to claim 1,
It is characterized in that, in the step 1), the solvent of addition is methanol, ethyl alcohol, tetrahydrofuran, any one in toluene, water, institute
The ammonolysis reaction temperature stated is 0-50 DEG C.
3. the synthetic method of 4,6-, bis- chloro- 1H- imidazos [4,5-C] pyridine -2 (3H) -one according to claim 2,
It is characterized in that, in the step 1), the solvent of addition is ethyl alcohol, then passes to ammonia ammonolysis；The ammonolysis reaction temperature
It is 15-30 DEG C.
4. the synthesis side of bis- chloro- 1H- imidazos [4,5-C] pyridine -2 (3H) -one of 4,6- according to claim 1 or 2 or 3
Method, which is characterized in that alkali is ethylenediamine, triethylamine, isopropylamine, DBU (1,8- diazabicylos 11 in the step 2)
Carbon -7- alkene), LDA (lithium diisopropylamine), butyl lithium, lithium hexamethyldisilazide, any one in sodium hydrogen be described
Reaction temperature be -10-50 DEG C.
5. the synthetic method of 4,6-, bis- chloro- 1H- imidazos [4,5-C] pyridine -2 (3H) -one according to claim 4,
It is characterized in that, alkali is LDA or lithium hexamethyldisilazide in the step 2), and the reaction temperature is 0-20 DEG C.
6. the conjunction of bis- chloro- 1H- imidazos [4,5-C] pyridine -2 (3H) -one of 4,6- according to claims 1 or 2 or 3 or 5
At method, which is characterized in that in the step 2), compound 2 under alkaline condition, carries out Hoffmann rearrangement reaction, in weight
Cyclization is heated after row obtains compound 3；In above-mentioned reaction, the reagent is sodium hypochlorite, any one in sodium hypobromite；
Be temperature it is 50-100 DEG C resetting the reaction in cyclization stage.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5424432A (en) * | 1994-05-26 | 1995-06-13 | Merck & Co., Inc. | Process for the preparation of imidazolutidine |
| CN101090902A (en) * | 2004-10-13 | 2007-12-19 | 默克公司 | Cgrp receptor antagonists |
| CN106831768A (en) * | 2017-01-06 | 2017-06-13 | 瑞孚信江苏药业股份有限公司 | A kind of synthetic method of 2,6 dichloropyridines [3,4 B] pyrazine |
| CN107778314A (en) * | 2016-08-29 | 2018-03-09 | 湖南华腾制药有限公司 | A kind of synthetic method of imidazopyridine derivatives |
-
2018
- 2018-04-20 CN CN201810362760.5A patent/CN108440522A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5424432A (en) * | 1994-05-26 | 1995-06-13 | Merck & Co., Inc. | Process for the preparation of imidazolutidine |
| CN101090902A (en) * | 2004-10-13 | 2007-12-19 | 默克公司 | Cgrp receptor antagonists |
| CN107778314A (en) * | 2016-08-29 | 2018-03-09 | 湖南华腾制药有限公司 | A kind of synthetic method of imidazopyridine derivatives |
| CN106831768A (en) * | 2017-01-06 | 2017-06-13 | 瑞孚信江苏药业股份有限公司 | A kind of synthetic method of 2,6 dichloropyridines [3,4 B] pyrazine |
Non-Patent Citations (2)
| Title |
|---|
| L.SELEY等: "Design and Synthesis of a Series of Chlorinated 3-Deazaadenine Analogues", 《NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS》 * |
| 何敬文等: "《药物合成》", 30 September 2013, 中国轻工业出版社 * |
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