CN103880740A - Synthesis of 4-nitro-3-hydroxy-2-picolinic acid - Google Patents
Synthesis of 4-nitro-3-hydroxy-2-picolinic acid Download PDFInfo
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- CN103880740A CN103880740A CN201410147498.4A CN201410147498A CN103880740A CN 103880740 A CN103880740 A CN 103880740A CN 201410147498 A CN201410147498 A CN 201410147498A CN 103880740 A CN103880740 A CN 103880740A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
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Abstract
The invention discloses a synthesis method of 4-nitro-3-hydroxy-2-picolinic acid. The synthesis method is characterized in that 3-hydroxy-2-picolinic acid is used as a starting material, the sulfonation reaction, nitratlon reaction and desulfonation reaction are carried out, and then the 4-nitro-3-hydroxy-2-picolinic acid is highly selectively obtained. The synthesis method is high in yield, and the synthesized 4-nitro-3-hydroxy-2-picolinic acid is high in quality.
Description
Technical field
The present invention relates to a kind of synthetic method of pyridine carboxylic acid, particularly the synthetic method of 4-nitro-3-hydroxyl-2-pyridine carboxylic acid.
Background technology
Pyridine carboxylic acid is important fine-chemical intermediate, is widely used at medicine and pesticide field.The pyridine carboxylic acid of hydroxyl is due to the response characteristic of hydroxyl and carboxyl, very extensive in field application such as fine chemicals, medicine, agricultural chemicals, functional materialss especially.Existing lot of documents has been reported the application of 3-hydroxyl-2-pyridine carboxylic acid.For example: United States Patent (USP) (US2005/192294) has reported that employing 3-hydroxyl-2-pyridine carboxylic acid and ethanol synthesis generate 3-hydroxyl-2-pyridine carboxylic acid ethyl ester; United States Patent (USP) (US2008/262224) has reported that employing 3-hydroxyl-2-pyridine carboxylic acid and methyl-magnesium-bromide generate 3-hydroxyl-2-acetylpyridine; World patent (WO2009/150144) has reported that employing 3-hydroxyl-2-pyridine carboxylic acid and NBS carry out the synthetic bromo-3-hydroxyl-2-of the 6-pyridine carboxylic acid of bromo-reaction; But also there is no up to now the bibliographical information about 3-hydroxyl-2-pyridine carboxylic acid nitration reaction efficient synthesis.
On the other hand, equally also there is lot of documents to report the synthetic and application of 3-nitro 2 hydroxybenzoic acid (being 3-Nitrosalicylic Acid).For example: document (Synthetic Communications; Vol. 35; Nb. 2; (2005); P263-270) report that employing Whitfield's ointment is raw material, with Zn (NO
3)
2* 2N
2o
4as nitrating agent, carry out nitration reaction and obtain the mixture of 3-nitro 2 hydroxybenzoic acid and 5-nitro 2 hydroxybenzoic acid.Document (Chemistry-A European Journal; Vol. 16; Nb. 8; (2010); P2366 – 23701) report that employing 3-nitro 2-bromo-benzoic acid is raw material, under cuprous oxide catalysis condition, hydrolysis obtains 3-Nitrosalicylic Acid.Document (Journal of the Chemical Society; (1952); P 4368,4371) report that employing 3-nitro 2-chloro-benzoic acid is raw material, cuprous iodide catalytic hydrolysis obtains 3-Nitrosalicylic Acid.
Although compound 4-nitro-3-hydroxyl-2-pyridine carboxylic acid (molecular formula C that the present invention reports
6h
4n
2o
5) and above-mentioned compound 3-Nitrosalicylic Acid (the molecular formula C mentioning
7h
5nO
5) similar, but their maximum difference is that the six-ring of 3-Nitrosalicylic Acid is phenyl ring, and the six-ring of 4-nitro-3-hydroxyl-2-pyridine carboxylic acid is pyridine heterocycle.As everyone knows, the reactive behavior of pyridine heterocycle, location feature and phenyl ring are far from each other, and therefore the method for synthetic 3-Nitrosalicylic Acid does not almost have a reference value for synthetic 4-nitro-3-hydroxyl-2-pyridine carboxylic acid.
Therefore, also without any the efficient synthesis of bibliographical information 4-nitro-3-hydroxyl-2-pyridine carboxylic acid of publishing, do not have similar synthetic method to use for reference up to now yet.But 4-nitro-3-hydroxyl-2-pyridine carboxylic acid is owing to containing multiple active reactive groups such as carboxyl, hydroxyl, nitro in its structure simultaneously, is important reaction intermediate, very extensive in field application such as medicine, agricultural chemicals, dyestuff, functional materialss.The present invention is intended to report a kind of chemical synthesis process of high selectivity 4-nitro-3-hydroxyl-2-pyridine carboxylic acid.
At first, our reference literature (Organic Letters; 2008, vol. 10; Nb. 22; P5127-5130) the synthetic thinking of document of 3-Nitrosalicylic Acid, adopting 3-hydroxyl-2-pyridine carboxylic acid is starting raw material, the vitriol oil, concentrated nitric acid are nitrating agent, methylene dichloride is solvent (formula 1), under heating condition, react, not only yield is very low to find this reaction, and generates a large amount of isomers 6-nitro-3-hydroxyl-2-pyridine carboxylic acids.The ratio of 4-nitro-3-hydroxyl-2-pyridine carboxylic acid and 6-nitro-3-hydroxyl-2-pyridine carboxylic acid is 6:4, and because two compound polarity are close, separates very difficulty.Therefore, we have to further find effective means and carry out high selectivity 4-nitro-3-hydroxyl-2-pyridine carboxylic acid.
Summary of the invention
The object of the present invention is to provide the synthetic method of 4-nitro-3-hydroxyl-2-pyridine carboxylic acid that a kind of selectivity is good, simple to operate, yield is high.
The technical solution used in the present invention is as follows:
A synthetic method for 4-nitro-3-hydroxyl-2-pyridine carboxylic acid, the starting raw material adopting is 3-hydroxyl-2-pyridine carboxylic acid.3-hydroxyl-2-pyridine carboxylic acid is through sulfonation reaction, nitration reaction, de-sulfonation reaction, and last highly selective obtains 4-nitro-3-hydroxyl-2-pyridine carboxylic acid.
The synthetic 4-nitro-3-hydroxyl-2-pyridine carboxylic acid chemical reaction process of the present invention is as follows:
The concrete synthetic method of above-mentioned 4-nitro-3-hydroxyl-2-pyridine carboxylic acid is:
(1) sulfonation reaction: synthetic 6-sulfonic group-3-hydroxyl-2-pyridine carboxylic acid:
In three-necked bottle, add successively the vitriol oil, 3-hydroxyl-2-pyridine carboxylic acid, cuprous catalysis agent, be warmed up to 90-130 DEG C of reaction 2～5 hours, liquid chromatography monitors after 99% above raw material 3-hydroxyl-2-pyridine carboxylic acid generation sulfonation reaction, temperature is raised to 140 DEG C again, reaction 4-8 hour, liquid chromatography monitoring 4-sulfonic group-3-hydroxyl-2-pyridine carboxylic acid content is lower than after 0.5%, stopped reaction, drop to room temperature, reaction solution does not need further processing, is directly used in next step reaction.
(2) nitration reaction: synthetic 6-sulfonic group-4-nitro-3-hydroxyl-2-pyridine carboxylic acid:
The reaction solution that previous step sulfonation reaction obtains, add appropriate nitrate catalyst, heating in water bath to 40 DEG C, drip concentrated nitric acid, liquid chromatography monitors after 98% above intermediate 6-sulfonic group-3-hydroxyl-2-pyridine carboxylic acid generation nitration reaction, and stopped reaction, drops to room temperature, reaction solution does not need further processing equally, is directly used in next step reaction.
(3) de-sulfonation reaction: synthetic 4-nitro-3-hydroxyl-2-pyridine carboxylic acid:
The reaction solution that previous step nitration reaction obtains, under frozen water is cooling, drips and calculate water gaging, drip process temperature and be controlled at 60-80 DEG C, drip after water, temperature is raised to reaction at 130-160 DEG C, and liquid chromatography monitors 98% above intermediate 6-sulfonic group-4-nitro-3-hydroxyl-2-pyridine carboxylic acid and occurs after de-sulfonation reaction, stopped reaction, drop to room temperature, bathe and reaction solution is cooled to-5 DEG C with cryosel again, separate out a large amount of solids, suction filtration obtains 4-nitro-3-hydroxyl-2-pyridine carboxylic acid crude product.The mixed solvent recrystallization of isopropyl alcohol and water for crude product, obtains 4-nitro-3-hydroxyl-2-pyridine carboxylic acid sterling, and liquid phase analysis content is more than 95%.Three-step reaction total recovery 60～87%.
The agent of the above-mentioned sulfonation reaction cuprous catalysis of the present invention is one or more in cuprous chloride, cuprous bromide, Red copper oxide.Cuprous catalysis agent consumption is 0.5%～20% of starting raw material 3-hydroxyl-2-pyridine carboxylic acid quality, and wherein preferred scope is 2%～10%.
It is cerous nitrate (Ce (NO that the above-mentioned nitration reaction of the present invention newly adds nitrate catalyst
3)
3), zirconium nitrate (Zr (NO
3)
4), ceric ammonium nitrate ((NH
4)
2ce (NO
3)
6) in one or more.Nitrate catalyst consumption is 1%～60% of starting raw material 3-hydroxyl-2-pyridine carboxylic acid quality, and wherein preferred scope is 5%～30%.After the first step has been reacted, reaction system Central Asia copper catalyst is separated from reaction system, carry out again second step reaction, do not separate and directly carry out second step reaction with cuprous catalysis agent, contrast and experiment shows (referring to the embodiment of the present invention 1 and embodiment 8), and what in nitration reaction, play katalysis is combination catalyst: cuprous catalysis agent and nitrate catalyst.
The above-mentioned sulfonation reaction of the present invention, 90-130 DEG C of reaction 2～5 hours, liquid chromatography monitors after 99% above raw material 3-hydroxyl-2-pyridine carboxylic acid generation sulfonation reaction, only shows that sulfonation reaction occurs raw material 3-hydroxyl-2-pyridine carboxylic acid overwhelming majority, does not represent that this step sulfonation reaction finishes.Because hydroxyl is ortho-para directing group, now the product of sulfonation reaction has two, 6-sulfonic group-3-hydroxyl-2-pyridine carboxylic acid and 4-sulfonic group-3-hydroxyl-2-pyridine carboxylic acid (formula 3).On the other hand, 4-sulfonic group-3-hydroxyl-2-pyridine carboxylic acid is kinetic products, 6-sulfonic group-3-hydroxyl-2-pyridine carboxylic acid is Thermodynamically stable product, temperature is raised to 140 DEG C, while continuing reaction, can make 4-sulfonic group-3-hydroxyl-2-pyridine carboxylic acid be converted into 6-sulfonic group-3-hydroxyl-2-pyridine carboxylic acid (formula 4) completely, such experimental implementation process has been guaranteed the purity of final product, therefore adopt synthetic method of the present invention, isomers impurity in the product 4-nitro-3-hydroxyl-2-pyridine carboxylic acid obtaining after recrystallization (6-nitro-3-hydroxyl-2-pyridine carboxylic acid) content is lower than 0.1%.
Therefore, the present invention has good economic benefit and social benefit in sum.
Embodiment is by the following examples described in further detail foregoing of the present invention again.But this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following instance.Without departing from the idea case in the present invention described above, various replacements or the change made according to ordinary skill knowledge and customary means, all should comprise within the scope of the invention.
Embodiment
Embodiment 1
(1) sulfonation reaction: synthetic 6-sulfonic group-3-hydroxyl-2-pyridine carboxylic acid:
In 2000 milliliters of three-necked bottles, add successively 500 milliliters of vitriol oils, 3-hydroxyl-2-pyridine carboxylic acid 69.56g(0.5mol), catalyzer cuprous chloride 6.96g, be warmed up to 120 DEG C of reactions 3.5 hours, it is 99.2% that liquid chromatography monitors raw material 3-hydroxyl-2-pyridine carboxylic acid transformation efficiency, temperature is raised to 140 DEG C again, react 5 hours, liquid chromatography monitoring 4-sulfonic group-3-hydroxyl-2-pyridine carboxylic acid content is 0.3%, stopped reaction, drop to room temperature, reaction solution does not need further processing, is directly used in next step reaction.
(2) nitration reaction: synthetic 6-sulfonic group-4-nitro-3-hydroxyl-2-pyridine carboxylic acid:
The reaction solution that previous step sulfonation reaction obtains, adds catalyzer cerous nitrate (Ce (NO
3)
3) 13.91g, heating in water bath to 40 DEG C, drip concentrated nitric acid 92.60g, drip 3 hours used times, after dripping, continue reaction 2 hours at 40 DEG C, be warmed up to 55 DEG C of reactions 1 hour, it is 98.9% that liquid chromatography monitors intermediate 6-sulfonic group-3-hydroxyl-2-pyridine carboxylic acid transformation efficiency, and stopped reaction, drops to room temperature, reaction solution does not need further processing equally, is directly used in next step reaction.
(3) de-sulfonation reaction: synthetic 4-nitro-3-hydroxyl-2-pyridine carboxylic acid:
The reaction solution that previous step nitration reaction obtains, under frozen water is cooling, slowly drips water 346.50g, dropping process very exothermic, temperature is controlled at below 70 DEG C, drips after water, and temperature is raised to 140 DEG C of reactions 10 hours, it is 98.6% that liquid chromatography monitors intermediate 6-sulfonic group-4-nitro-3-hydroxyl-2-pyridine carboxylic acid transformation efficiency, stopped reaction, drops to room temperature, then bathes and reaction solution is cooled to-5 DEG C with cryosel, separate out a large amount of solids, suction filtration obtains 4-nitro-3-hydroxyl-2-pyridine carboxylic acid crude product.Mixed solvent (massfraction of Virahol the is 20%) recrystallization of isopropyl alcohol and water for crude product, obtains light yellow 4-nitro-3-hydroxyl-2-pyridine carboxylic acid sterling 77.05g, liquid phase analysis content 99.4%, three-step reaction total recovery 83.7%.Product fusing point: 155～157 DEG C; MS (ES): m/z=185.0[M+H]
+.
1HNMR(400MHz,?DMSO-
d6)?δppm?10.52?(s,?br,?1H)；8.47-8.41?(d,?1H，J=8.5Hz),?7.48-7.46?(d,?1H，J=8.5Hz)。
13CNMR(400MHz,?CDCl
3)δppm?169.2，153.8,?146.3,?142.3,?139.9,?125.1。
Embodiment 2
In sulfonation reaction, adding catalyzer is cuprous bromide 6.96g, and other operate with embodiment 1.
Operate according to embodiment 1, obtain light yellow 4-nitro-3-hydroxyl-2-pyridine carboxylic acid sterling 79.26g, liquid phase analysis content 99.3%, three-step reaction total recovery 86.1%.
Embodiment 3
In nitration reaction, adding catalyzer is zirconium nitrate (Zr (NO
3)
4) 13.91g, other biconditional operations embodiment 1.
Operate according to embodiment 1, obtain light yellow 4-nitro-3-hydroxyl-2-pyridine carboxylic acid sterling 72.82g, liquid phase analysis content 99.2%, three-step reaction total recovery 79.1%.
Embodiment 4
In nitration reaction, adding catalyzer is ceric ammonium nitrate ((NH
4)
2ce (NO
3)
6) 13.91g, other biconditional operations embodiment 1.
Operate according to embodiment 1, obtain light yellow 4-nitro-3-hydroxyl-2-pyridine carboxylic acid sterling 67.02g, liquid phase analysis content 98.1%, three-step reaction total recovery 72.8%.
Embodiment 5
In sulfonation reaction, adding catalyzer is Red copper oxide 6.96g, and other operate with embodiment 1.
Operate according to embodiment 1, obtain light yellow 4-nitro-3-hydroxyl-2-pyridine carboxylic acid sterling 57.58g, liquid phase analysis content 97.3%, three-step reaction total recovery 62.6%.
Embodiment 6
In sulfonation reaction, adding catalyzer is cuprous bromide 1.39g, and other operate with embodiment 1.
Operate according to embodiment 1, obtain light yellow 4-nitro-3-hydroxyl-2-pyridine carboxylic acid sterling 51.73g, liquid phase analysis content 98.0%, three-step reaction total recovery 56.2%.
Embodiment 7
In nitration reaction, adding catalyzer is cerous nitrate (Ce (NO
3)
3) 3.48g, other biconditional operations embodiment 1.
Operate according to embodiment 1, obtain light yellow 4-nitro-3-hydroxyl-2-pyridine carboxylic acid sterling 61.86g, liquid phase analysis content 98.0%, three-step reaction total recovery 67.2%.
Embodiment 8
(1) sulfonation reaction: synthetic 6-sulfonic group-3-hydroxyl-2-pyridine carboxylic acid:
In 2000 milliliters of three-necked bottles, add successively 500 milliliters of vitriol oils, 3-hydroxyl-2-pyridine carboxylic acid 69.56g(0.5mol), catalyzer cuprous chloride 6.96g, be warmed up to 120 DEG C of reactions 3.5 hours, it is 99.2% that liquid chromatography monitors raw material 3-hydroxyl-2-pyridine carboxylic acid transformation efficiency, temperature is raised to 140 DEG C again, react 5 hours, liquid chromatography monitoring 4-sulfonic group-3-hydroxyl-2-pyridine carboxylic acid content is 0.3%, stopped reaction, drop to room temperature, under frozen water is cooling, slowly drip water 1000g, dropping process very exothermic, temperature is controlled at below 50 DEG C, after water droplet adds, drop to room temperature, with 30% aqueous sodium hydroxide solution adjusting pH=3, adopt a large amount of trichloromethanes, repeatedly extraction in batches, until more than 99% 6-sulfonic group-3-hydroxyl-2-pyridine carboxylic acid in the aqueous solution is extracted in organic phase, revolve to steam and remove extraction agent trichloromethane, obtain solid 6-sulfonic group-3-hydroxyl-2-pyridine carboxylic acid, be directly used in next step nitration reaction.
(2) nitration reaction: synthetic 6-sulfonic group-4-nitro-3-hydroxyl-2-pyridine carboxylic acid:
The solid 6-sulfonic group-3-hydroxyl-2-pyridine carboxylic acid, the catalyzer cerous nitrate (Ce (NO that in 2000 milliliters of three-necked bottles, add successively 500 milliliters of vitriol oils, previous step sulfonation reaction to obtain
3)
3) 13.91g, heating in water bath to 40 DEG C, drip concentrated nitric acid 92.60g, drip 3 hours used times, after dripping, continue reaction 2 hours at 40 DEG C, be warmed up to 55 DEG C of reactions 1 hour, it is 99.2% that liquid chromatography monitors intermediate 6-sulfonic group-3-hydroxyl-2-pyridine carboxylic acid transformation efficiency, and stopped reaction, drops to room temperature, reaction solution does not need further processing equally, is directly used in next step reaction.
(3) de-sulfonation reaction: synthetic 4-nitro-3-hydroxyl-2-pyridine carboxylic acid:
The reaction solution that previous step nitration reaction obtains, under frozen water is cooling, slowly drips water 346.50g, dropping process very exothermic, temperature is controlled at below 70 DEG C, drips after water, and temperature is raised to 140 DEG C of reactions 10 hours, it is 98.5% that liquid chromatography monitors intermediate 6-sulfonic group-4-nitro-3-hydroxyl-2-pyridine carboxylic acid transformation efficiency, stopped reaction, drops to room temperature, then bathes and reaction solution is cooled to-5 DEG C with cryosel, separate out a large amount of solids, suction filtration obtains 4-nitro-3-hydroxyl-2-pyridine carboxylic acid crude product.Mixed solvent (massfraction of Virahol the is 20%) recrystallization of isopropyl alcohol and water for crude product, obtains light yellow 4-nitro-3-hydroxyl-2-pyridine carboxylic acid sterling 47.87g, liquid phase analysis content 98.8%, three-step reaction total recovery 52.0%.Product fusing point: 155～157 DEG C.
Claims (4)
- The synthetic method of 1.4-nitro-3-hydroxyl-2-pyridine carboxylic acid, concrete steps are:(1) sulfonation reaction: synthetic 6-sulfonic group-3-hydroxyl-2-pyridine carboxylic acid:In three-necked bottle, add successively the vitriol oil, 3-hydroxyl-2-pyridine carboxylic acid, cuprous catalysis agent, be warmed up to 90-130 DEG C of reaction 2～5 hours, liquid chromatography monitors after 99% above raw material 3-hydroxyl-2-pyridine carboxylic acid generation sulfonation reaction, temperature is raised to 140 DEG C again, reaction 4-8 hour, liquid chromatography monitoring 4-sulfonic group-3-hydroxyl-2-pyridine carboxylic acid content is lower than after 0.5%, stopped reaction, drop to room temperature, reaction solution does not need further processing, is directly used in next step reaction;(2) nitration reaction: synthetic 6-sulfonic group-4-nitro-3-hydroxyl-2-pyridine carboxylic acid:The reaction solution that previous step sulfonation reaction obtains, add appropriate nitrate catalyst, heating in water bath to 40 DEG C, drip concentrated nitric acid, liquid chromatography monitors after 98% above intermediate 6-sulfonic group-3-hydroxyl-2-pyridine carboxylic acid generation nitration reaction, and stopped reaction, drops to room temperature, reaction solution does not need further processing equally, is directly used in next step reaction;(3) de-sulfonation reaction: synthetic 4-nitro-3-hydroxyl-2-pyridine carboxylic acid:The reaction solution that previous step nitration reaction obtains, under frozen water is cooling, drip and calculate water gaging, drip process temperature and be controlled at 60-80 DEG C, drip after water, temperature is raised to reaction at 130-160 DEG C, liquid chromatography monitors 98% above intermediate 6-sulfonic group-4-nitro-3-hydroxyl-2-pyridine carboxylic acid and occurs after de-sulfonation reaction, stopped reaction, drop to room temperature, bathe and reaction solution is cooled to-5 DEG C with cryosel again, separate out a large amount of solids, suction filtration obtains 4-nitro-3-hydroxyl-2-pyridine carboxylic acid crude product, the mixed solvent recrystallization of isopropyl alcohol and water for crude product, obtain 4-nitro-3-hydroxyl-2-pyridine carboxylic acid sterling, liquid phase analysis content is more than 95%, three-step reaction total recovery 60～87%.
- 2. described in claim 1 in sulfonation reaction, cuprous catalysis agent is one or more in cuprous chloride, cuprous bromide, Red copper oxide; Cuprous catalysis agent consumption is 0.5%～20% of starting raw material 3-hydroxyl-2-pyridine carboxylic acid quality.
- 3. described in claim 1 in nitration reaction, newly adding nitrate catalyst is cerous nitrate (Ce (NO 3) 3), zirconium nitrate (Zr (NO 3) 4), ceric ammonium nitrate ((NH 4) 2ce (NO 3) 6) in one or more; Nitrate catalyst consumption is 1%～60% of starting raw material 3-hydroxyl-2-pyridine carboxylic acid quality.
- 4. described in claim 1 in sulfonation reaction, catalyzer is the combination catalyst of cuprous catalysis agent and phase-transfer catalyst; Wherein phase-transfer catalyst is one or more in crown ether benzo 18 hats six, crown ether benzo 15 hats five, quaternary ammonium salt Tetrabutyl amonium bromide, quaternary ammonium salt benzyltriethylammoinium chloride, quaternary ammonium salt tetrabutylammonium chloride, quaternary ammonium salt tetramethyl ammonium chloride, quaternary ammonium salt etamon chloride, quaternary ammonium salt 4 bromide, quaternary ammonium salt tetraethylammonium bromide; Phase-transfer catalyst consumption is 0.1%～5% of starting raw material 3-hydroxyl-2-pyridine carboxylic acid quality.
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Cited By (3)
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| CN104140394A (en) * | 2014-07-22 | 2014-11-12 | 中北大学 | Preparation method of 1-methyl-3,4,5-trinitro-pyrazole |
| CN110803991A (en) * | 2019-12-03 | 2020-02-18 | 江西西林科股份有限公司 | Method for synthesizing isooctyl nitrate by micro-reaction technology |
| CN112194618A (en) * | 2020-12-03 | 2021-01-08 | 苏州开元民生科技股份有限公司 | Preparation method of 2, 3-dichloropyridine |
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