CN106831768A - A kind of synthetic method of 2,6 dichloropyridines [3,4 B] pyrazine - Google Patents
A kind of synthetic method of 2,6 dichloropyridines [3,4 B] pyrazine Download PDFInfo
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- 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
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Abstract
The invention discloses a kind of 2; 6 dichloropyridines [3; 4 B] pyrazine synthetic method, be predominant starting material with the pyridine carboxylic acid of 3 amino 4, through over-churning; chloro; ammonolysis, BOC protections, the reaction such as Hoffmann rearrangement and cyclization obtains target compound; although route of the present invention relatively has route steps will grow two steps, the substantially protection of amino and deprotection；Whole route is substantially unit process, and simple to operate, mild condition just can obtain target compound through simple process, and whole piece route yield is higher；Carrying out production with the route will bring very big economic benefit and social benefit.Synthetic method of the invention has the characteristics that in a word：Reaction condition is gentle, and technological operation is simple, environmental protection, low cost, high income.
Description
Technical field
It is the conjunction of one kind 2,6- dichloropyridine [3,4-B] pyrazine specifically the present invention relates to a kind of chemical synthesis process
Into method.
Background technology
2,6- dichloropyridines [3,4-B] pyrazine, is the autoimmune diseases such as treatment rheumatoid arthritis and lupus erythematosus
The important intermediate of new drug, No. CAS is [1379338-74-5], and molecular formula is as follows.
The compound is directed to the new height of EGFR-TK Syk (spleen tyrosine kinase) in B-cell receptor signal path
Selective micromolecular inhibitor, is mainly used in the autoimmune diseases such as treatment rheumatoid arthritis and lupus erythematosus.The medicine be after
It is new after Mabthera, anti-TNF alpha medicine infliximab, adalimumab and Etanercept Syk (spleen tyrosine kinase)
High selectivity micromolecular inhibitor, for treating the autoimmune diseases such as rheumatoid arthritis and lupus erythematosus.Its chemical name
For：(S)-{ 7- [4- (1- mesyl-4- piperidyls)-phenyl]-pyridine [3,4-B] pyrazinyl }-morpholine -2-methylamine, molecule
Structural formula is as follows：
2,6- dichloropyridines [3,4-B] pyrazine, is the important intermediate of the new drug.Document reports 2,6- dichloropyridines [3,4-
B] pyrazine synthetic method mainly has a kind:The chloro- 4-aminopyridine methods of 2,6- bis-.
2,6- bis- chloro- 4-aminopyridine methods are for raw material, through nitrification, rearrangement, reduction with the chloro- 4-aminopyridine methods of 2,6- bis-
Synthesize 2,6- dichloropyridine [3,4-B] pyrazine with the step of cyclization 4.The method process route is short, and total recovery is primarily now preferably
Synthetic route.This technique, for initiation material, is carried out with concentrated nitric acid with the chloro- 4-aminopyridine methods of 2,6- bis- under the conditions of the concentrated sulfuric acid
Nitration reaction obtains product 2, and then rearrangement reaction obtains compound 3.By the prepare compound of compound 3 in the presence of metallic reducing agent
4, compound 4 obtains product 5 with glyoxal care：2,6- dichloropyridines [3,4-B] pyrazine.Route is as follows：
The various method surveys for preparing 2,6- dichloropyridines [3,4-B] pyrazine are as follows.
1.WO2012123312 is reported with the chloro- 4-aminopyridine methods of 2,6- bis- as initiation material, and 2 are obtained through the reaction of 4 steps,
6- dichloropyridines [3,4-B] pyrazine, wherein employs stannous chloride reduction in the last two steps and condensation ring-closure reaction prepares product,
Reaction dissolvent used is ethanol.
2.WO2012107423 is reported with the chloro- 4-aminopyridine methods of 2,6- bis- as initiation material, and 2 are obtained through the reaction of 4 steps,
6- dichloropyridines [3,4-B] pyrazine, wherein employs iron powder reducing in the last two steps and condensation ring-closure reaction prepares product, used
Reaction dissolvent is ethanol,
3.WO2012167733 is reported with the chloro- 4-aminopyridine methods of 2,6- bis- as initiation material, and 2 are obtained through the reaction of 4 steps,
6- dichloropyridines [3,4-B] pyrazine, wherein employs iron powder reducing in the last two steps and condensation ring-closure reaction prepares product, used
Reaction dissolvent is isopropanol,
4.US20140121200 is reported with the chloro- 4-aminopyridine methods of 2,6- bis- as initiation material, is obtained through the reaction of 4 steps
2,6- dichloropyridines [3,4-B] pyrazine, wherein employs metallic reducing agent in the last two steps and condensation ring-closure reaction prepares product,
Reaction dissolvent used is polar solvent,
The preparation method of 2,6- dichloropyridine [3,4-B] pyrazine is summarized, is original predominantly with the chloro- 4-aminopyridines of 2,6- bis-
Material prepares 2,6- dichloropyridine [3,4-B] pyrazine using condensation ring-closure reaction.The reaction used in this synthetic reaction route is molten
Agent is respectively methyl alcohol, absolute ethyl alcohol, alcohol-water etc., has used relatively large number of organic solvent, relatively costly.Simultaneously in nitrification
It is a large amount of with rearrangement reaction to use sulfuric acid, nitric acid to produce a large amount of waste water；Other initiation material price is higher, causes whole production
High cost.Therefore all there are various defects in existing synthetic method, or yield is relatively low, or organic solvent is too
It is many, cause cost costly.Existing technology path is being required for improving in terms of environment friendly and cost.
The content of the invention
The present invention is directed to problems of the prior art, there is provided a kind of 2,6- dichloropyridines simple to operate, low cost
The synthetic route of [3,4-B] pyrazine.
The present invention is realized to reach above-mentioned purpose by such technical scheme：
The invention discloses the synthetic method of one kind 2,6- dichloropyridine [3,4-B] pyrazine, with 3- amino-Isonicotinic acid
It is predominant starting material, through over-churning, chloro, ammonolysis, BOC protections, the reaction such as Hoffmann rearrangement and cyclization obtains target chemical combination
Thing, chemical equation is as follows：
Preparation process is as follows：
1), in reaction bulb, substrate and methyl alcohol are added, stirs molten clear, plus catalytic reagent, to react and obtain compound 1 after terminating；
2), compound 1 adds DMF (N,N-dimethylformamide), is subsequently adding halogenating agent；Feed intake to be reacted after finishing and continue
A few houres, react the compound 2 through post-processing after terminating；
3), compound 2 adds ammonolysis solution, terminates through monitoring reaction, and conventional treatment obtains compound 3；
4), compound 3 obtains compound 4 with BOC (two t-butyl carbonates) under alkali effect；
5), compound 4 sloughs BOC in the effect of acid, obtains compound 5；
6), compound 5 obtains target compound with glyoxal effect.
As further improving, step 1 of the present invention) in, catalyst be sulfuric acid, hydrochloric acid, nitric acid, acetic acid, first
Sulfonic acid, thionyl chloride, oxalyl chloride, any one in POCl3, esterification reaction temperature is 0-100 DEG C.
Used as further improving, catalyst of the present invention is thionyl chloride or oxalyl chloride, and optimal reaction temperature is
60-70℃。
As further improving, step 2 of the present invention) in, the reaction temperature in halo stage is 5-60 DEG C, halogenation
Agent is phosphorus pentachloride, POCl3, thionyl chloride, chlorine, two chlordantoins, any one in chlorosuccinimide.
Used as further improving, reaction temperature of the present invention is 15-30 DEG C, and halo agent is two chlordantoins or chloro
Succimide.
As further improving, step 3 of the present invention) in, the solvent of addition is methyl alcohol, ethanol, tetrahydrofuran,
Any one in toluene, water, ammonolysis reaction temperature is 0-50 DEG C.
As further improving, step 3 of the present invention) in, the solvent of addition is ethanol, then passes to ammonia ammonia
Solution；Reaction temperature is 15-30 DEG C.
As further improving, step 4 of the present invention) in alkali be ethylenediamine, triethylamine, isopropylamine, DBU (1,
Carbon -7- the alkene of 8- diazabicylos 11), LDA (lithium diisopropylamine), butyl lithium, lithium hexamethyldisilazide, in sodium hydrogen
Any one, -10-50 DEG C of reaction temperature.
As further improving, step 4 of the present invention) in alkali be LDA or lithium hexamethyldisilazide, reaction
Temperature is 0-20 DEG C.
As further improving, step 5 of the present invention) in, the synthesis of compound 5 in the basic conditions, is added
Substrate carries out Hofmann reaction, and finally directly de- BOC obtains compound 5 after rearrangement；In above-mentioned reaction, reagent used is secondary
Sodium chlorate, sodium hypobromite, NaOH, potassium hydroxide, sodium methoxide, caustic alcohol, potassium tert-butoxide is any one in sodium tert-butoxide
Kind；Reaction temperature is divided into two sections, and in generation isocyanide acid phase, reaction temperature is -15-10 DEG C, in the rearrangement temperature in the stage of rearrangement
It is 30-100 DEG C.
As further improving, step 5 of the present invention) in, reagent is sodium methoxide or caustic alcohol, reaction temperature
It it is -5-5 DEG C, it is 50-60 DEG C to reset temperature.
As further improving, step 6 of the present invention) in, the alcohol of compound 5 dissolves in reaction, is subsequently adding
The solution of aldehyde, after monitoring reaction terminates, the product of filtering, alcohol used is methyl alcohol, ethanol, propyl alcohol, isopropanol, tertiary fourth in reaction
Alcohol, any one in n-butanol, reaction temperature is 40-100 DEG C.
As further improving, step 6 of the present invention) in, alcohol used is isopropanol, and reaction temperature is 70-
85℃。
Beneficial effects of the present invention are as follows:
Synthetic method of the invention, is with 3- amino-Isonicotinic acid as predominant starting material, with methyl alcohol in catalyst
The lower esterification of effect, ester is can be obtained by by simple process, then directly carries out chloro, under suitable conditions, the operation of this step
, to the disagreeableness reagent of environment, simple BOC protections are subsequently carried out without using chlorine etc., then obtained with Hoffmann rearrangement
Ammonia, the waste water of generation is less.Take off BOC in acid condition again and obtain diamino, without the obvious waste gas of generation.Relative to original
Technique, this route is without largely using sulfuric acid and nitric acid, it is to avoid one of hazardous reaction in iodine：Nitration reaction.Together
When this route using the low rearrangement reaction of energy consumption, so as to reduce production cost.
Although this route relatively has route steps will grow two steps, the substantially protection of amino and deprotection；Whole road
Line is substantially unit process, simple to operate, mild condition, and target compound, whole piece route yield are just can obtain through simple process
It is higher；Carrying out production with the route will bring very big economic benefit and social benefit.Synthetic method of the invention in a word
Have the characteristics that：Reaction condition is gentle, and technological operation is simple, environmental protection, low cost, high income.
Specific embodiment
The present invention is described in further detail with reference to embodiment, but the scope of the present invention is not limited to implement
Example.
Embodiment 1
1) in equipped with mechanical agitation, reflux condensing tube, the four-hole boiling flask of thermometer, 20 grams of substrate adds 60 grams of methyl alcohol,
Stirring is decreased slightly as temperature to complete molten, and 20 grams of thionyl chloride is added dropwise, and stirs 20min.60-70 DEG C of insulation reaction 10h is warmed up to, monitoring is anti-
After should terminating, cooling is distilled off solvent, post-processes residue, and filtering, washing, drying obtain compound 1 and amount to 21.15
Gram, in terms of 3- amino-Isonicotinic acid, yield is 96%.
2) in equipped with mechanical agitation, reflux condensing tube, the four-hole boiling flask of thermometer, 20 g of compound 1 are put into 40 grams
In DMF, stirring adds 19 grams of N- chlorosuccinimides to complete molten, cooling, and 60min is stirred in continuation.20 DEG C are warming up to, in 20-
30 DEG C of insulation reaction 3h, after chloro is complete, cooling, concentration and recovery major part solvent, residue into water is filtered, is washed,
Drying, obtains compound 2 and amounts to 27.9 grams, and in terms of compound 1, yield is 96%.
3) in equipped with mechanical agitation, reflux condensing tube, the four-hole boiling flask of thermometer, 20 g of compound 2 are put into 30 grams
In ethanol, stirring is warming up to 20 DEG C to complete molten, is passed through ammonia, is then incubated 12h at 20-30 DEG C, after ammonolysis are complete, will be organic
Solvent recovery, residue cooling, filtering, washing, drying obtain compound 3 and amount to 17.26 grams, and in terms of compound 2, yield is
92.6%.
4) in equipped with mechanical agitation, reflux condensing tube, the four-hole boiling flask of thermometer, 20 g of compound 3 are put into 30 grams
In tetrahydrofuran, stirring adds alkali to complete molten.Cooling, is added dropwise 23.3 grams of BOC acid anhydrides, stirs 30min.15 DEG C are warming up to,
15-20 DEG C of insulation 6h, after reaction completely, reclaims organic solvent.After recovery is finished, part water is added, filtrate is adjusted with NaOH
PH to 8-9, is then extracted with ethyl acetate, and organic layer is water-washed away with salt, and concentration is dry, is obtained compound 4 and is amounted to 27.3 grams, to change
Compound 3 is counted, and yield is 92%.
5) in equipped with mechanical agitation, reflux condensing tube, the four-hole boiling flask of thermometer, during 20 g of compound 4 are put into water,
Stirring, cooling is added dropwise fresh sodium methoxide, and after being added dropwise to complete, insulated and stirred is stirred 2 hours.After reaction terminates, 50 are warming up to
DEG C, 3h is incubated at 50-60 DEG C, after reaction completely, organic solvent is reclaimed in cooling.After recovery is finished, part water, Ran Houyong are added
Ethyl acetate is extracted, and organic layer is water-washed away with salt, and concentration is dry, is obtained compound 5 and is amounted to 9.88 grams, and in terms of compound 4, yield is
85%.
6) in equipped with mechanical agitation, reflux condensing tube, the four-hole boiling flask of thermometer, 10 g of compound 5 are put into isopropyl
In 30 grams of alcohol, stirring adds glyoxal water solution, is warming up to 80 DEG C, and 12h, after reaction completely, cooling, mistake are incubated at 80-83 DEG C
Filter, filter cake is washed with isopropanol, and drying obtains compound 6 and amounts to 10.11 grams, and in terms of compound 5, yield is 90%.
Embodiment 2
1) in equipped with mechanical agitation, reflux condensing tube, the four-hole boiling flask of thermometer, 20 grams of substrate adds 60 grams of methyl alcohol,
Stirring is decreased slightly as temperature to complete molten, and 19 grams of oxalyl chloride is added dropwise, and stirs 20min.It is warmed up to 90-100 DEG C of insulation reaction 8h, monitoring reaction
After end, cooling is distilled off solvent, post-processes residue, and filtering, washing, drying obtain compound 1 and amount to 20.9 grams, with
3- amino-Isonicotinic acid meter, yield is 95%.
2) in equipped with mechanical agitation, reflux condensing tube, the four-hole boiling flask of thermometer, 20 g of compound 1 are put into 40 grams
In DMF, stirring adds 13.2 grams of two chlordantoin to complete molten, cooling, and 60min is stirred in continuation.50 DEG C are warming up to, in 50-60 DEG C of guarantor
Warm to react 3h, after chloro is complete, cooling, concentration and recovery major part solvent by residue into water, is filtered, washs, dried,
Obtain compound 2 and amount to 27.7 grams, in terms of compound 1, yield is 95.3%.
3) in equipped with mechanical agitation, reflux condensing tube, the four-hole boiling flask of thermometer, 20 g of compound 2 are put into 30 grams
In ethanol, stirring is warming up to 40 DEG C to complete molten, is passed through ammonia, is then incubated 24h at 40-50 DEG C, after ammonolysis are complete, will be organic
Solvent recovery, residue cooling, filtering, washing, drying obtain compound 3 and amount to 17.1 grams, and in terms of compound 2, yield is
92.0%.
4) in equipped with mechanical agitation, reflux condensing tube, the four-hole boiling flask of thermometer, 20 g of compound 3 are put into 30 grams
In tetrahydrofuran, stirring to complete molten, cooling, addition lithium hexamethyldisilazide.23.3 grams of BOC acid anhydrides, stirring is added dropwise
30min.- 10 DEG C are warming up to, 6h is incubated at -10-0 DEG C, after reaction completely, reclaim organic solvent.After recovery is finished, part is added
Water, filtrate adjusts PH to 8-9 with NaOH, is then extracted with ethyl acetate, and organic layer is water-washed away with salt, and concentration is dry, is changed
Compound 4 amounts to 27.1 grams, and in terms of compound 3, yield is 91.2%.
5) in equipped with mechanical agitation, reflux condensing tube, the four-hole boiling flask of thermometer, during 20 g of compound 4 are put into water,
Stirring, cooling is added dropwise caustic alcohol, and after being added dropwise to complete, insulated and stirred is stirred 2 hours.After reaction terminates, 70 DEG C are warming up to, in 70-
80 DEG C of insulation 6h, after reaction completely, organic solvent is reclaimed in cooling.After recovery is finished, part water is added, then use ethyl acetate
Extraction, organic layer is water-washed away with salt, and concentration is dry, is obtained compound 5 and is amounted to 9.5 grams, and in terms of compound 4, yield is 82%.
6) in equipped with mechanical agitation, reflux condensing tube, the four-hole boiling flask of thermometer, 10 g of compound 5 are put into ethanol
In 30 grams, stirring adds glyoxal water solution, is warming up to 40 DEG C, and 12h, after reaction completely, cooling, mistake are incubated at 40-45 DEG C
Filter, filter cake is washed with ethanol, and drying obtains compound 6 and amounts to 9.5 grams, and in terms of compound 5, yield is 84.6%.
Embodiment 3
1) in equipped with mechanical agitation, reflux condensing tube, the four-hole boiling flask of thermometer, 20 grams of substrate adds 60 grams of methyl alcohol,
Stirring is decreased slightly as temperature to complete molten, and 20 grams of thionyl chloride is added dropwise, and stirs 20min.It is warmed up to 0-10 DEG C of insulation reaction 10h, monitoring reaction
After end, cooling is distilled off solvent, post-processes residue, and filtering, washing, drying obtain compound 1 and amount to 20.05 grams,
In terms of 3- amino-Isonicotinic acid, yield is 90.9%.
2) in equipped with mechanical agitation, reflux condensing tube, the four-hole boiling flask of thermometer, 20 g of compound 1 are put into 40 grams
In DMF, stirring adds 19 grams of N- chlorosuccinimides to complete molten, cooling, and 60min is stirred in continuation.5 DEG C are warming up to, in 5-10
DEG C insulation reaction 3h, after chloro is complete, cooling, concentration and recovery major part solvent by residue into water, filtering, washing, dries
It is dry, obtain compound 2 and amount to 26 grams, in terms of compound 1, yield is 89.5%.
3) in equipped with mechanical agitation, reflux condensing tube, the four-hole boiling flask of thermometer, 20 g of compound 2 are put into 30 grams
In ethanol, stirring is warming up to 0 DEG C to complete molten, is passed through ammonia, is then incubated 12h at 0-10 DEG C, after ammonolysis are complete, will be organic molten
Agent is reclaimed, residue cooling, and filtering, washing, drying obtain compound 3 and amount to 16.23 grams, and in terms of compound 2, yield is
87.1%.
4) in equipped with mechanical agitation, reflux condensing tube, the four-hole boiling flask of thermometer, 20 g of compound 3 are put into 30 grams
In tetrahydrofuran, stirring adds alkali to complete molten.Cooling, is added dropwise 23.3 grams of BOC acid anhydrides, stirs 30min.40 DEG C are warming up to,
40-50 DEG C of insulation 6h, after reaction completely, reclaims organic solvent.After recovery is finished, part water is added, filtrate is adjusted with NaOH
PH to 8-9, is then extracted with ethyl acetate, and organic layer is water-washed away with salt, and concentration is dry, is obtained compound 4 and is amounted to 26.3 grams, to change
Compound 3 is counted, and yield is 88.63%.
5) in equipped with mechanical agitation, reflux condensing tube, the four-hole boiling flask of thermometer, during 20 g of compound 4 are put into water,
Stirring, cooling is added dropwise fresh sodium methoxide, and after being added dropwise to complete, insulated and stirred is stirred 2 hours.After reaction terminates, 30 are warming up to
DEG C, 2h is incubated at 30-40 DEG C, after reaction completely, organic solvent is reclaimed in cooling.After recovery is finished, part water, Ran Houyong are added
Ethyl acetate is extracted, and organic layer is water-washed away with salt, and concentration is dry, is obtained compound 5 and is amounted to 9.52 grams, and in terms of compound 4, yield is
81.9%.
6) in equipped with mechanical agitation, reflux condensing tube, the four-hole boiling flask of thermometer, 10 g of compound 5 are put into tertiary fourth
In 30 grams of alcohol, stirring adds glyoxal water solution, is warming up to 90 DEG C, and 12h is incubated at 90-100 DEG C, after reaction completely, cooling,
Filtering, filter cake is washed with the tert-butyl alcohol, and drying obtains compound 6 and amounts to 10.0 grams, and in terms of compound 5, yield is 89%.
Listed above is only several specific embodiments of the invention.It is clear that the invention is not restricted to above example, can be with
There are many deformations, all changes that one of ordinary skill in the art can directly derive from present disclosure or associate
Shape, is considered as protection scope of the present invention.
Claims (13)
1. one kind 2, the synthetic method of 6- dichloropyridines [3,4-B] pyrazine, it is characterised in that be with 3- amino-Isonicotinic acid
Predominant starting material, through over-churning, chloro, ammonolysis, BOC protections, the reaction such as Hoffmann rearrangement and cyclization obtains target compound,
Chemical equation is as follows：
Preparation process is as follows：
1), in reaction bulb, substrate and methyl alcohol are added, stirs molten clear, plus catalytic reagent, to react and obtain compound 1 after terminating；
2), compound 1 adds DMF (N,N-dimethylformamide), is subsequently adding halogenating agent；Feeding intake, it is lasting several small reacted after finishing
When, react the compound 2 through post-processing after terminating；
3), compound 2 adds ammonolysis solution, terminates through monitoring reaction, and conventional treatment obtains compound 3；
4), compound 3 obtains compound 4 with BOC (two t-butyl carbonates) under alkali effect；
5), compound 4 sloughs BOC in the effect of acid, obtains compound 5；
6), compound 5 obtains target compound with glyoxal effect.
2. the synthetic method of 2,6- dichloropyridines [3,4-B] pyrazine according to claim 1, it is characterised in that described
Step 1) in, catalyst be sulfuric acid, hydrochloric acid, nitric acid, acetic acid, methanesulfonic acid, thionyl chloride, oxalyl chloride is any in POCl3
One kind, described esterification reaction temperature is 0-100 DEG C.
3. the synthetic method of 2,6- dichloropyridines [3,4-B] pyrazine according to claim 2, it is characterised in that described
Catalyst is thionyl chloride or oxalyl chloride, and optimal reaction temperature is 60-70 DEG C.
4. the synthetic method of 2,6- dichloropyridines [3, the 4-B] pyrazine according to claim 1 or 2 or 3, it is characterised in that
Described step 2) in, the reaction temperature in halo stage is 5-60 DEG C, and halogenating agent is phosphorus pentachloride, POCl3, thionyl chloride,
Chlorine, two chlordantoins, any one in chlorosuccinimide.
5. the synthetic method of 2,6- dichloropyridines [3,4-B] pyrazine according to claim 4, it is characterised in that described
Reaction temperature is 15-30 DEG C, and described halo agent is two chlordantoins or chlorosuccinimide.
6. the synthetic method of 2,6- dichloropyridines [3,4-B] pyrazine according to claim 1, it is characterised in that described
Step 3) in, the solvent of addition is methyl alcohol, ethanol, tetrahydrofuran, any one in toluene, water, and ammonolysis reaction temperature is 0-
50℃。
7. the synthetic method of 2,6- dichloropyridines [3,4-B] pyrazine according to claim 6, it is characterised in that described
Step 3) in, the solvent of addition is ethanol, then passes to ammonia ammonolysis；Described reaction temperature is 15-30 DEG C.
8. the synthetic method of 2,6- dichloropyridines [3,4-B] pyrazine according to claim 1, it is characterised in that described
Step 4) in alkali be ethylenediamine, triethylamine, isopropylamine, DBU (carbon -7- alkene of 1,8- diazabicylo 11), LDA (diisopropyls
Lithium amide), butyl lithium, lithium hexamethyldisilazide, any one in sodium hydrogen, -10-50 DEG C of described reaction temperature.
9. the synthetic method of 2,6- dichloropyridines [3,4-B] pyrazine according to claim 8, it is characterised in that described
Step 4) in alkali be LDA or lithium hexamethyldisilazide, described reaction temperature is 0-20 DEG C.
10. the synthetic method of 2,6- dichloropyridines [3,4-B] pyrazine according to claim 1, it is characterised in that described
Step 5) in, the synthesis of compound 5 in the basic conditions, adds substrate to carry out Hofmann reaction, finally directly takes off after rearrangement
BOC obtains compound 5；In above-mentioned reaction, reagent used is sodium hypochlorite, sodium hypobromite, NaOH, potassium hydroxide, first
Sodium alkoxide, caustic alcohol, potassium tert-butoxide, any one in sodium tert-butoxide；Reaction temperature is divided into two sections, in generation isocyanide acid phase,
Reaction temperature is -15-10 DEG C, is 30-100 DEG C in the rearrangement temperature in the stage of rearrangement.
The synthetic method of 11. 2,6- dichloropyridines [3,4-B] pyrazines according to claim 10, it is characterised in that described
The step of 5) in, reagent is sodium methoxide or caustic alcohol, and described reaction temperature is -5-5 DEG C, and it is 50-60 DEG C to reset temperature.
The synthetic method of 12. 2,6- dichloropyridines [3,4-B] pyrazines according to claim 1, it is characterised in that described
Step 6) in, the alcohol of compound 5 dissolves in reaction, is subsequently adding the solution of aldehyde, after monitoring reaction terminates, the product of filtering, instead
Should in alcohol used be methyl alcohol, ethanol, propyl alcohol, isopropanol, the tert-butyl alcohol, any one in n-butanol, reaction temperature is 40-
100℃。
The synthetic method of 13. 2,6- dichloropyridines [3,4-B] pyrazines according to claim 12, it is characterised in that described
The step of 6) in, alcohol used is isopropanol, and reaction temperature is 70-85 DEG C.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| CN112159368A (en) * | 2020-07-07 | 2021-01-01 | 杭州杜易科技有限公司 | Synthesis method of linezolid intermediate |
| CN112851677A (en) * | 2019-11-26 | 2021-05-28 | 中国科学院大连化学物理研究所 | Synthesis method of imidazopyridine or pyrimidine derivative |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108440522A (en) * | 2018-04-20 | 2018-08-24 | 瑞孚信江苏药业股份有限公司 | A kind of bis- chloro- 1H- imidazos [4,5-C] pyridines -2 of 4,6-（3H）The synthetic method of -one |
| CN112851677A (en) * | 2019-11-26 | 2021-05-28 | 中国科学院大连化学物理研究所 | Synthesis method of imidazopyridine or pyrimidine derivative |
| CN112159368A (en) * | 2020-07-07 | 2021-01-01 | 杭州杜易科技有限公司 | Synthesis method of linezolid intermediate |
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