CN107628990A - The synthetic method of the formaldehyde of 5 bromopyridine 3 - Google Patents
The synthetic method of the formaldehyde of 5 bromopyridine 3 Download PDFInfo
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- CN107628990A CN107628990A CN201711103036.2A CN201711103036A CN107628990A CN 107628990 A CN107628990 A CN 107628990A CN 201711103036 A CN201711103036 A CN 201711103036A CN 107628990 A CN107628990 A CN 107628990A
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- formaldehyde
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Abstract
The invention belongs to organic synthesis field, more particularly to a kind of synthetic method of the formaldehyde of 5 bromopyridine 3, with 3,5 dibromo pyridines are raw material, and tetramethylethylenediamine is stabilizer, and product is prepared with form reagent reacting, the presence of tetramethylethylenediamine reduces the impurity in product, improves yield；Synthetic method is not high to temperature requirement, can be completed under conditions of 5 25 DEG C, saves energy consumption, easily operated；In synthesis technique, post-processing approach is simple, step is few, high income, is adapted to industrialized production.
Description
Technical field
The invention belongs to organic synthesis field, more particularly to a kind of synthetic method of 5- bromopyridines -3- formaldehyde.
Background technology
In the prior art, the synthetic method of 5- bromopyridines -3- formaldehyde has a variety of；Document report is using 3,5- dibromo pyridines as original
Expect, with butyl lithium bromine lithium exchange system for 5- bromopyridine -3- formaldehyde (bibliography under the conditions of ultralow temperature (- 78 DEG C)：Non-
symmetrical,potentially redox non-innocent imino NHC pyridine'pincers'via a
zinc ion template-assisted synthesis.Simler,Thomas et al.Dalton Transactions,
46(18),5955-5964；2017), another document report with 3,5- dibromo pyridines for raw material, at a temperature of -15 DEG C, butyl
Lithium coordinates with n-butylmagnesium chloride magnesium, synthesizes 5- bromopyridine -3- formaldehyde (bibliography：process for preparation of
functionalized pyridylamines from halopyridines.Hagadorn,John Robert et
al.U.S.Pat.Appl.Publ.,20090082573,26Mar 2009)；Above two synthetic method is reacted in ultralow temperature bar
It could be carried out under part, severe reaction conditions, it is difficult to industrialize；Also document report is using the bromo- 3- picolines of 5- as raw material, dioxy
Change selenolite and be combined to 5- bromopyridine -3- formaldehyde (bibliography：Preparation of
heterocyclyloxyphenoxyethyl substituted pyrimidine-2,4(1H,3H)-diones for
treating HIV infections.Jorgensen,William L.and Anderson,Karen
S.U.S.Pat.Appl.Publ.,20150105351,16Apr 2015)；But a large amount of selenic acid derivatives invest in the course of reaction
Reactor inwall, post processing are very difficult；Also a kind of synthetic method is using 5- methyl -3- aminopyridines as raw material, is passed through successively
Bromo, hydrolysis twice, obtain product (bibliography：Stilbene heterocycles:synthesis,antimicrobial,
antioxidant and anticancer activities.Reddy,G.Chandrasekara et al。Pharma
Innovation,3(12-A),24-30；2015), but this method step is more, and yield is low.
The content of the invention
The present invention solves above-mentioned technical problem present in prior art, there is provided a kind of synthesis of 5- bromopyridines -3- formaldehyde
Method.
To solve the above problems, technical scheme is as follows：
A kind of synthetic method of 5- bromopyridines -3- formaldehyde, comprises the following steps：
Synthetic route：
S1, by 3,5- dibromo pyridines, tetrahydrofuran (THF), tetramethylethylenediamine is well mixed, and is cooled to ice-water bath
10-15℃；The volume ratio of the 3,5- dibromo pyridines and tetrahydrofuran is 1:3-6,3, the 5- dibromo pyridines and tetramethyl second
The mass ratio of diamines is 1:0.5-1；
S2, grignard reagent is taken, instilled in reaction solution made from step 1, reaction temperature maintains less than 15 DEG C；
S3, step 2 gained reaction solution maintain 20-25 DEG C of reaction 1-2h, and reaction solution is cooled to 5-10 DEG C with ice-water bath；
S4, DMF (DMF) is taken, be dissolved in THF, THF is used for the concentration for diluting DMF, when preventing from being added dropwise
Vigorous reaction, DMF-THF mixed liquors are slowly added dropwise in step 3 gained reaction solution, maintain after 10-15 DEG C of reaction 30min,
Reaction solution separating-purifying obtains 5- bromopyridine -3- formaldehyde crude products；
The 3,5- dibromo pyridines, RMgBr, DMF the ratio between mole are 1:1.2-1.5:1.5-2.
Preferably, the method for the gained reaction solution separating-purifying of above-mentioned steps 4 is：Reaction solution is poured into frozen water, stirred
10min., stand, liquid separation, organic phase is washed, dry, is evaporated under reduced pressure, 5- bromopyridine -3- formaldehyde crude products are made；Received to improve
Rate, aqueous phase obtained by liquid separation can be also extracted with ethyl acetate once, organic phase is washed, dry, is evaporated under reduced pressure；It is highly preferred that
The volume of the frozen water is 1.5-4 times of tetrahydrofuran volume in reaction solution.
Preferably, the method for purification of the 5- bromopyridines -3- formaldehyde crude products is：Petroleum ether (PE) is added in crude product:Acetic acid
Ethyl ester (EA)=6:1(W:W) mixed solvent, 20-25 DEG C of mashing 1h, filters, washs, drying；It is highly preferred that the petroleum ether/
The addition of ethyl acetate mixed solvent is：Every gram of 5- bromopyridine -3- formaldehyde crude product adds 1-2ml petrol ether/ethyl acetates and mixed
Bonding solvent.
Preferably, the grignard reagent is selected from isopropyl magnesium bromide, methyl-magnesium-bromide, methyl-magnesium-chloride or isopropyl chlorination
Any one in magnesium.
Relative to prior art, advantages of the present invention is as follows,
The method of present invention synthesis 5- bromopyridine -3- formaldehyde, with 3,5- dibromo pyridines for raw material, tetramethylethylenediamine is steady
Determine agent, prepare product with form reagent reacting, the presence of tetramethylethylenediamine reduces the impurity in product, improves yield；
Synthetic method is not high to temperature requirement, can be completed under conditions of 5-25 DEG C, saves energy consumption, easily operated；
In synthesis technique, post-processing approach is simple, step is few, high income, is adapted to industrialized production.
Embodiment
Embodiment 1：
3,5- dibromo pyridine 250g, tetrahydrofuran 1000ml, tetramethylethylenediamine 150g are taken, puts into 5L reaction bulbs, opens
Open stirring.System ice-water bath is cooled to 10-15 DEG C.Isopropylmagnesium chloride (2.6M, THF) 750ml is taken, is instilled in reaction solution, dimension
Hold below 15 DEG C and (slightly heat up).Drop finishes, and removes ice-water bath, maintains 20-25 DEG C of reaction 1-2h.Reaction solution is cooled to ice-water bath
5-10℃.DMF 130g are taken, are dissolved in 100ml THF.DMF-THF mixed liquors are slowly added dropwise in reaction solution, it is warm in maintenance
Less than 15 DEG C (heat release, should be slowly added dropwise).Drop finishes, and maintains 10-15 DEG C of reaction 30min..Reaction solution is poured into 2L frozen water, stirred
10min. is mixed, is stood, liquid separation, collects aqueous phase and organic phase respectively.Aqueous phase 1L ethyl acetate extracts once, merges organic phase.Have
Machine is mutually washed with 1L water, 1L saturated brines successively, anhydrous sodium sulfate drying.50-55 DEG C of vacuum distillation, obtains taupe crude product.Slightly
PE is added in product:EA=6:1(W:W) mixed solvent 200ml, 20-25 DEG C of mashing 1h.Filtering, filter cake elute one with 50ml PE
It is secondary.Infrared lamp is dried, and obtains canescence to off-white powder, 112g, yield 67.3%.
Embodiment 2：
With embodiment 1, only will
The volume ratio of 3,5- dibromo pyridines and tetrahydrofuran is revised as：1:3
The mass ratio of 3,5- dibromo pyridines and tetramethylethylenediamine is revised as 1:0.5；
3,5- dibromo pyridines, isopropylmagnesium chloride, DMF the ratio between mole are revised as 1:1.2-:1.5；
The volume of frozen water is 1.5 times of tetrahydrofuran volume in reaction solution.
The yield of target product is 65.4%.
Embodiment 3：
With embodiment 1, only will
The volume ratio of 3,5- dibromo pyridines and tetrahydrofuran is revised as：1:6
The mass ratio of 3,5- dibromo pyridines and tetramethylethylenediamine is revised as 1:1；
3,5- dibromo pyridines, isopropylmagnesium chloride, DMF the ratio between mole are revised as 1:1.5:2；
The volume of frozen water is 4 times of tetrahydrofuran volume in reaction solution.
The yield of target product is 66.3%.
Embodiment 4：
With embodiment 1, only made from isopropyl magnesium bromide, methyl-magnesium-bromide, methyl-magnesium-chloride instead of isopropylmagnesium chloride
Reaction is participated in for grignard reagent, target product yield is respectively 62.9%, 64.1%, 63.8%.
Comparative example 1：
In the synthetic method of the present invention, tetramethylethylenediamine has an impact, if not as stabilizer to reaction ultimate yield
Add tetramethylethylenediamine, obtained crude product impurity is more, and yield is low.
3,5- dibromo pyridine 250g, tetrahydrofuran 1000ml are taken, is put into 5L reaction bulbs, opens stirring.System ice-water bath
It is cooled to 10-15 DEG C.Isopropylmagnesium chloride (2.6M, THF) 750ml is taken, is instilled in reaction solution, is maintained less than 15 DEG C and (slightly rise
Temperature).Drop finishes, and removes ice-water bath, maintains 20-25 DEG C of reaction 1-2h.Reaction solution is cooled to 5-10 DEG C with ice-water bath.Take DMF130g,
It is dissolved in 100ml THF.DMF-THF mixed liquors (dilution DMF concentration, vigorous reaction when preventing from being added dropwise) are slowly added dropwise into anti-
Answer in liquid, in maintenance warm less than 15 DEG C (heat release, should be slowly added dropwise).Drop finishes, and maintains 10-15 DEG C of reaction 30min..By reaction solution
Pour into 2L frozen water, stir 10min., stand, liquid separation, collect aqueous phase and organic phase respectively.Aqueous phase 1L ethyl acetate extraction one
It is secondary, merge organic phase.Organic phase is washed with 1L water, 1L saturated brines successively, anhydrous sodium sulfate drying.50-55 DEG C of vacuum distillation,
Obtain taupe crude product.PE is added in crude product:EA=6:1(W:W) mixed solvent 200ml, 20-25 DEG C of mashing 1h.Filtering, filter cake with
50ml PE are eluted once.Infrared lamp is dried, and obtains canescence to off-white powder, 34g, yield 17.4%.
Comparative example 2：
In the synthetic method of the present invention, the selection of grignard reagent has an impact to reaction ultimate yield；Positive fourth is selected respectively
Base magnesium bromide, n-butylmagnesium chloride magnesium participate in reaction as grignard reagent, and yield is low.
RMgBr selects normal-butyl magnesium bromide
3,5- dibromo pyridine 250g, tetrahydrofuran 1000ml, tetramethylethylenediamine 150g are taken, is put into 5L reaction bulbs, body
It is that ice-water bath is cooled to 10-15 DEG C.Take normal-butyl magnesium bromide (2.6M, THF) 750ml, instill in reaction solution, maintain 15 DEG C with
Under (slightly heat up).Drop finishes, and removes ice-water bath, maintains 20-25 DEG C of reaction 1-2h.Reaction solution is cooled to 5-10 DEG C with ice-water bath.Take
DMF 130g, it is dissolved in 100ml THF.DMF-THF mixed liquors (dilution DMF concentration, vigorous reaction when preventing from being added dropwise) is slow
Slowly it is added dropwise in reaction solution, in maintenance warm less than 15 DEG C (heat release, should be slowly added dropwise).Drop finishes, and maintains 10-15 DEG C of reaction
30min..Reaction solution is poured into 2L frozen water, stirs 10min., is stood, liquid separation, collects aqueous phase and organic phase respectively.Aqueous phase 1L
Ethyl acetate extracts once, merges organic phase.Organic phase is washed with 1L water, 1L saturated brines successively, anhydrous sodium sulfate drying.
50-55 DEG C of vacuum distillation, obtains taupe crude product.PE is added in crude product:EA=6:1(W:W) mixed solvent 200ml, 20-25 DEG C are beaten
Starch 1h.Filtering, filter cake are eluted once with 50ml PE.Infrared lamp is dried, and obtains canescence to off-white powder, 42g, yield
21.5%.
RMgBr selects n-butylmagnesium chloride magnesium
3,5- dibromo pyridine 250g, tetrahydrofuran 1000ml, tetramethylethylenediamine 150g are taken, is put into 5L reaction bulbs, body
It is that ice-water bath is cooled to 10-15 DEG C.Take n-butylmagnesium chloride magnesium (2.6M, THF) 750ml, instill in reaction solution, maintain 15 DEG C with
Under (slightly heat up).Drop finishes, and removes ice-water bath, maintains 20-25 DEG C of reaction 1-2h.Reaction solution is cooled to 5-10 DEG C with ice-water bath.Take
DMF 130g, it is dissolved in 100ml THF.DMF-THF mixed liquors (dilution DMF concentration, vigorous reaction when preventing from being added dropwise) is slow
Slowly it is added dropwise in reaction solution, in maintenance warm less than 15 DEG C (heat release, should be slowly added dropwise).Drop finishes, and maintains 10-15 DEG C of reaction
30min..Reaction solution is poured into 2L frozen water, stirs 10min., is stood, liquid separation, collects aqueous phase and organic phase respectively.Aqueous phase 1L
Ethyl acetate extracts once, merges organic phase.Organic phase is washed with 1L water, 1L saturated brines successively, anhydrous sodium sulfate drying.
50-55 DEG C of vacuum distillation, obtains taupe crude product.PE is added in crude product:EA=6:1(W:W) mixed solvent 200ml, 20-25 DEG C are beaten
Starch 1h.Filtering, filter cake are eluted once with 50ml PE.Infrared lamp is dried, and obtains canescence to off-white powder, 44g, yield
22.5%.
Comparative example 3：
In the synthetic method of the present invention, temperature when RMgBr is added dropwise has an impact to reaction ultimate yield；With implementation
Example 1, it is 30 DEG C or 50 DEG C only to change temperature when RMgBr is added dropwise：
At 30 DEG C, crude product impurity content is more；Yield 27.8%；
At 50 DEG C, many impurity, product is seldom, yield 10.2%；.
It should be noted that above-described embodiment is only presently preferred embodiments of the present invention, it is not used for limiting the present invention's
Protection domain, the equivalent substitution or replacement made on the basis of the above belong to protection scope of the present invention.
Claims (8)
1. a kind of synthetic method of 5- bromopyridines -3- formaldehyde, it is characterised in that comprise the following steps：
Synthetic route：
S1,3,5- dibromo pyridines, tetrahydrofuran, tetramethylethylenediamine be well mixed, 10-15 DEG C is cooled to ice-water bath；Institute
The volume ratio for stating 3,5- dibromo pyridines and tetrahydrofuran is 1:3-6, the quality of 3, the 5- dibromo pyridines and tetramethylethylenediamine
Than for 1:0.5-1；
S2, RMgBr is taken, instilled in reaction solution made from step 1, reaction temperature maintains less than 15 DEG C；
S3, step 2 gained reaction solution maintain 20-25 DEG C of reaction 1-2h, and reaction solution is cooled to 5-10 DEG C with ice-water bath；
S4, take DMF to be added dropwise in step 3 gained reaction solution, maintain after 10-15 DEG C of reaction 30min, reaction
Liquid separating-purifying obtains 5- bromopyridine -3- formaldehyde crude products；
The 3,5- dibromo pyridines, RMgBr, DMF the ratio between mole are 1:1.2-1.5:1.5-2.
2. the synthetic method of 5- bromopyridines -3- formaldehyde as claimed in claim 1, it is characterised in that in the step 4, N, N-
Dimethylformamide is first dissolved in tetrahydrofuran before adding reaction solution.
3. the synthetic method of 5- bromopyridines -3- formaldehyde as claimed in claim 1, it is characterised in that reacted obtained by the step 4
The method of liquid separating-purifying is：Reaction solution is poured into frozen water, stirs 10min., stands, liquid separation, organic phase is washed, dry, subtracted
Pressure distillation, is made 5- bromopyridine -3- formaldehyde crude products.
4. the synthetic method of 5- bromopyridines -3- formaldehyde as claimed in claim 3, it is characterised in that use aqueous phase obtained by liquid separation
Ethyl acetate is extracted once, and organic phase is washed, dry, is evaporated under reduced pressure；5- bromopyridine -3- formaldehyde crude products are made.
5. the synthetic method of 5- bromopyridines -3- formaldehyde as claimed in claim 3, it is characterised in that the volume of the frozen water is
1.5-4 times of tetrahydrofuran volume in reaction solution.
6. the synthetic method of the 5- bromopyridine -3- formaldehyde as described in claim 3 or 4, it is characterised in that the 5- bromopyridines -
The method of purification of 3- formaldehyde crude products is：Petroleum ether is added in crude product:Ethyl acetate=6:1(W:W) mixed solvent, 20-25 DEG C is beaten
1h is starched, is filtered, is washed, drying.
7. the synthetic method of 5- bromopyridines -3- formaldehyde as claimed in claim 6, it is characterised in that the petroleum ether/acetic acid second
The addition of ester mixed solvent is：Every gram of 5- bromopyridine -3- formaldehyde crude product adds 1-2ml petrol ether/ethyl acetate mixed solvents.
8. the synthetic method of 5- bromopyridines -3- formaldehyde as claimed in claim 1, it is characterised in that the grignard reagent is selected from
Any one in isopropyl magnesium bromide, methyl-magnesium-bromide, methyl-magnesium-chloride or isopropylmagnesium chloride.
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| CN112479991A (en) * | 2020-12-28 | 2021-03-12 | 重庆三圣实业股份有限公司 | Preparation method of 2-bromo-5-aldehyde pyridine |
| CN113135899A (en) * | 2021-06-21 | 2021-07-20 | 北京鑫开元医药科技有限公司 | Benzocycloheptapyridine compounds, process for their preparation and their use |
| CN115010656A (en) * | 2022-06-14 | 2022-09-06 | 苏州昊帆生物股份有限公司 | Preparation method of 5-acetyl-2-bromopyridine |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112479991A (en) * | 2020-12-28 | 2021-03-12 | 重庆三圣实业股份有限公司 | Preparation method of 2-bromo-5-aldehyde pyridine |
| CN113135899A (en) * | 2021-06-21 | 2021-07-20 | 北京鑫开元医药科技有限公司 | Benzocycloheptapyridine compounds, process for their preparation and their use |
| CN113135899B (en) * | 2021-06-21 | 2021-11-23 | 北京鑫开元医药科技有限公司 | Benzocycloheptapyridine compounds, process for their preparation and their use |
| CN115010656A (en) * | 2022-06-14 | 2022-09-06 | 苏州昊帆生物股份有限公司 | Preparation method of 5-acetyl-2-bromopyridine |
| CN115010656B (en) * | 2022-06-14 | 2024-04-26 | 苏州昊帆生物股份有限公司 | Preparation method of 5-acetyl-2-bromopyridine |
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