CN104370807B - The synthetic method of a kind of 6-hydroxyl-5-nitronicotinic acid and process for separation and purification thereof - Google Patents
The synthetic method of a kind of 6-hydroxyl-5-nitronicotinic acid and process for separation and purification thereof Download PDFInfo
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- CN104370807B CN104370807B CN201410640447.5A CN201410640447A CN104370807B CN 104370807 B CN104370807 B CN 104370807B CN 201410640447 A CN201410640447 A CN 201410640447A CN 104370807 B CN104370807 B CN 104370807B
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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
- C07D213/80—Acids; Esters in position 3
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Abstract
The invention discloses synthetic method and the process for separation and purification thereof of a kind of 6 hydroxyl 5 nitronicotinic acid, belong to field of fine chemical.The method is with 6 hydroxy niacins as raw material, obtain highly purified product 6 hydroxyl 5 nitronicotinic acid through steps such as pre-nitration reaction, nitration reaction, Crystallization Separation purifying under the effect of the concentrated sulfuric acid and red fuming nitric acid (RFNA) and catalyst sulfuric acid hydrogen ammonium, with the purity requirement to intermediate for the synthesis field of satisfied medicine.The synthetic method of the present invention has the advantages such as the product purity that synthesis technique is simple, mild condition, productivity are high, obtain is high, easily operated, is suitable for industrialization and produces.
Description
Technical field
The invention belongs to field of fine chemical, specifically, relate to the synthetic method of a kind of chemical intermediate, more specifically,
Relate to synthetic method and the process for separation and purification thereof of a kind of 6-hydroxyl-5-nitronicotinic acid.
Background technology
Pyridine carboxylic acid compounds is important fine-chemical intermediate, is widely used with pesticide field at medicine.Hydroxyl and nitro
Pyridine carboxylic acid compounds due to the response characteristic of hydroxyl and carboxyl, especially fine chemicals, medicine synthesis, agricultural chemicals, work(
Can apply widely in the field such as material preparation and dyestuff intermediate.The general method synthesizing this compounds is mainly by nitre
Changing reaction introducing nitro on pyridine heterocycle to obtain, conventional method is to carry out nitrification with nitric acid in concentrated sulfuric acid, but mainly obtains
To be 4 or 2 be the pyridine of nitro or 2 and 5 pyridines being nitro, if to obtain 5 is nitro
Pyridine compounds, then reaction condition is just relatively harsher or agents useful for same is worth higher.
Through retrieval, Chinese Patent Application No. 201410186063.0 discloses the synthesis of a kind of 6-nitro-3-hydroxyl-2-pyridine carboxylic acid
Process for separation and purification, this invention is with 3-hydroxyl-2-pyridine carboxylic acid as initiation material, and the concentrated sulfuric acid is solvent, and red fuming nitric acid (RFNA) is nitrating agent,
In the presence of combination catalyst catalysis, the nitration reaction mixture (mixture-3-hydroxyl-2-of nitro containing 6-being generated by nitration reaction
Pyridine carboxylic acid and 4-nitro-3-hydroxyl-2-pyridine carboxylic acid), and isolated and purified from mixture further obtain high-purity 6-nitro-3-
The method of hydroxyl-2-pyridine carboxylic acid, although the compound structure very class of the 6-nitro-3-hydroxyl-2-pyridine carboxylic acid of this invention and the present invention
Seemingly, it is well known that, on pyridine heterocycle, the reactivity of different carbon atoms is big especially with localization characteristics otherness, the closer to pyrrole
The carbon atom of piperidinyl is more difficult to introduce other groups.The open a kind of nitropyridine class chemical combination of Chinese Patent Application No. 201010548270.8
The synthetic method of thing, 2-amino-nitro pyridine compounds and their is initiation material, obtains purpose of the present invention product nitre through single step reaction
Yl pyridines compounds, but the compound by-product being obtained by this reaction path is many, hardly results in 5 substituted pyridine first
Acid compounds, and there is no suitable product isolation and purification method.Therefore the method for above two compound is synthesized for synthesis
6-hydroxyl-5-nitronicotinic acid does not has a direct reference value, and do not have up to now any disclosed document or patent report high yield,
The effective ways of high yield synthesis 6-hydroxyl-5-nitronicotinic acid, not also being similar to synthetic method can directly use for reference.
Content of the invention
1. problem to be solved
Exist for existing nitrification synthetic method and be difficult to obtain 5 substituted pyridine carboxylic acid compounds and byproduct of reaction
Many, productivity is low, be difficult to the problems such as isolated and purified, the present invention provides synthetic method and the separation thereof of a kind of 6-hydroxyl-5-nitronicotinic acid
Method of purification, with 6-hydroxy niacin as raw material under the effect of catalyst, obtains height through nitration reaction and the isolated and purified of product
6-hydroxyl-5-the nitronicotinic acid of purity, with the purity requirement to intermediate for the synthesis field of satisfied medicine.
2. technical scheme
In order to solve the problems referred to above, the technical solution adopted in the present invention is as follows:
The synthetic method of a kind of 6-hydroxyl-5-nitronicotinic acid, the steps include:
A () is sequentially added into the concentrated sulfuric acid and red fuming nitric acid (RFNA) in reaction bulb, stir, and obtains reaction solution A, wherein the concentrated sulfuric acid with
The mol ratio of red fuming nitric acid (RFNA) is 1:(5-7)；
(b) by raw material 6-hydroxy niacin and catalyst sulfuric acid hydrogen ammonium according to mol ratio (50-70): 1 mixes, and is reacted
Raw material B；
C the reaction raw materials B obtaining in step (b), under conditions of stirring, is added the reaction obtaining in step (a) molten by ()
In liquid A, be then heated to 50-65 DEG C and carry out pre-nitration reaction, wherein the red fuming nitric acid (RFNA) in reaction solution A with in reaction raw materials B
6-hydroxy niacin mol ratio be (1.0-1.5): 1；
D () is by the 1:(5-7 in molar ratio of the concentrated sulfuric acid and red fuming nitric acid (RFNA)) mix, it is subsequently adding the stirring of catalyst sulfuric acid hydrogen ammonium
Uniformly obtaining reaction solution C, wherein red fuming nitric acid (RFNA) and the mol ratio of catalyst are (80-100): 1；
E the pre-nitration reaction in () step (c) terminates after, the reaction solution that will obtain in step (d) under conditions of stirring
C is added dropwise in the reaction bulb in step (c), is heated to 75-85 DEG C and carries out nitration reaction, obtains nitration reaction liquid；
F () carries out under the conditions of the nitration reaction liquid obtaining in step (e) is placed in 0-4 DEG C crystallizing 20-26h, after suction filtration separates
The solids obtaining is thick product first.
Preferably, in described step (a), the concentrated sulfuric acid and the volume ratio of red fuming nitric acid (RFNA) are 1:6.
Preferably, in described step (c), pre-nitration reaction temperature is 60 DEG C, and the reaction time is 4-5h.
Preferably, in described step (e), nitration reaction temperature is 80 DEG C, and the reaction time is 10-14h.
The process for separation and purification of the nitration reaction liquid of above-mentioned a kind of 6-hydroxyl-5-nitronicotinic acid, the steps include:
(1) rinse the thick product first obtaining in above-mentioned steps (f) with cold methanol, be then vacuum dried, obtain thick product second；
(2) by the thick product second obtaining in acidic aqueous solution dissolving step (2), then carry out isolated and purified with lowering temperature crystallization,
Crystallization temperature is 0-4 DEG C, finally obtains product 6-hydroxyl-5-nitronicotinic acid.
Preferably, in described step (2), the pH value of acidic aqueous solution is 1-4.
Preferably, in described step (2), cooling rate is 1 DEG C/min, and crystallization time is 10-14h.
Application in synthesis 6-hydroxyl-5-nitronicotinic acid for the ammonium hydrogen sulfate.
3. beneficial effect
Compared to prior art, the invention have the benefit that
(1) synthesizing the method for 6-hydroxyl-5-nitronicotinic acid in the present invention, inventor finds raw material 6-in long-term experiment is groped
Hydroxy niacin and product 6-hydroxyl-5-nitronicotinic acid and accessory substance are under different acid conditions, and solubility has significant difference,
Inventor analyzes also emphatically the change of reactant liquor acid-base value in building-up process, finally finds addition and the order of addition of the concentrated sulfuric acid
The yield and purity of product is had a great impact, particularly most important in terms of control dibit replaces the generation of nitro accessory substance；
(2) in the synthetic method of the present invention, with ammonium hydrogen sulfate as catalyst, first ammonium hydrogen sulfate is mixed with raw material, make to urge
Agent is fully contacted with raw material, then adds mixed raw material and catalyst and carries out nitration reaction in reactant liquor, promotes nitrification
The carrying out of reaction, improves the productivity of nitration reaction and the conversion ratio of product, and productivity can reach more than 90%, and conversion ratio is close
95%；
(3) synthetic method of the present invention is divided into pre-nitrification and two stages of nitrification, by the mixed liquor of the concentrated sulfuric acid and red fuming nitric acid (RFNA) and urge
Agent adds in two batches, and this synthesis mode can promote the conversion of product, improves conversion ratio and makes raw material reaction abundant；
(4) process for separation and purification of the nitration reaction liquid of the 6-hydroxyl-5-nitronicotinic acid of the present invention, in numerous studies, reaction is former
On the basis of material, product and accessory substance solubility in acid condition, molten for crystallization with the acid solution of suitable pH
Agent carries out Crystallization Separation after dissolving thick product again, makes product 6-hydroxyl-5-nitronicotinic acid preferential crystallization separate, finally obtains
6-hydroxyl-5-nitronicotinic acid purity, up to 99.5%, is entirely capable of meeting pharmaceutical synthesis needs.
Brief description
Fig. 1 is the schematic flow sheet of synthetic method of the present invention；
Fig. 2 is the structural representation of the present invention.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is further described below.
Embodiment 1
The synthetic method of a kind of 6-hydroxyl-5-nitronicotinic acid, the steps include:
A () is sequentially added into the concentrated sulfuric acid and red fuming nitric acid (RFNA) in reaction bulb, stir, and obtains reaction solution A, wherein the concentrated sulfuric acid with
The mol ratio of red fuming nitric acid (RFNA) is 1:6, and the mass fraction of the concentrated sulfuric acid used is 68%, and the mass fraction of red fuming nitric acid (RFNA) is 86%；
B raw material 6-hydroxy niacin and catalyst sulfuric acid hydrogen ammonium are mixed by () according to mol ratio 50:1, obtain reaction raw materials B；
C the reaction raw materials B obtaining in step (b), under conditions of stirring, is added the reaction obtaining in step (a) molten by ()
Liquid A, is then heated to 60 DEG C and carries out pre-nitration reaction 4h, the wherein HNO in reaction solution A3With in reaction raw materials B
The mol ratio of 6-hydroxy niacin is 1.5:1；
D the concentrated sulfuric acid is massaged by () with red fuming nitric acid (RFNA) (mass fraction of the concentrated sulfuric acid is 68%, and the mass fraction of red fuming nitric acid (RFNA) is 86%)
You mix than 1:6, are subsequently adding catalyst sulfuric acid hydrogen ammonium and are uniformly mixing to obtain reaction solution C, wherein red fuming nitric acid (RFNA) and sulfuric acid
The mol ratio of hydrogen ammonium is 80:1；
E the pre-nitration reaction in () step (c) terminates after, the reaction solution that will obtain in step (d) under conditions of stirring
C is added dropwise in the reaction bulb in step (c), is heated to 80 DEG C and carries out nitration reaction 12h, obtains nitration reaction liquid；
F the nitration reaction liquid obtaining in step (e) is placed in 0 DEG C and carries out crystallizing 24h by (), the solids that suction filtration obtains after separating
For thick product first.
The process for separation and purification of the nitration reaction liquid of above-mentioned a kind of 6-hydroxyl-5-nitronicotinic acid, the steps include:
(1) it by the thick product first obtaining in cold methanol (4 DEG C) rinsing above-mentioned steps (f), is then vacuum dried, is slightly produced
Product second；
(2) by the thick product second obtaining in acidic aqueous solution dissolving step (2) that pH value is 4, lowering temperature crystallization is then used
Carrying out isolated and purified, cooling rate is 1 DEG C/min, and crystallization temperature is 0 DEG C, and crystallization time is 12h, finally obtains product 6-
Hydroxyl-5-nitronicotinic acid.
In the present embodiment, the productivity of 6-hydroxyl-5-nitronicotinic acid is 88.24%, and conversion ratio is 94.86%, in the present embodiment
After isolation and purification method is isolated and purified, after testing, the purity of product 6-hydroxyl-5-nitronicotinic acid is 99.50%.
Embodiment 2
The synthetic method of a kind of 6-hydroxyl-5-nitronicotinic acid, the steps include:
A () is sequentially added into the concentrated sulfuric acid and red fuming nitric acid (RFNA) in reaction bulb, stir, and obtains reaction solution A, wherein the concentrated sulfuric acid with
The mol ratio of red fuming nitric acid (RFNA) is 1:5, and the mass fraction of the concentrated sulfuric acid used is 68%, and the mass fraction of red fuming nitric acid (RFNA) is 86%；
B raw material 6-hydroxy niacin and catalyst sulfuric acid hydrogen ammonium are mixed by () according to mol ratio 60:1, obtain reaction raw materials B；
C the reaction raw materials B obtaining in step (b), under conditions of stirring, is added the reaction obtaining in step (a) molten by ()
Liquid A, is then heated to 50 DEG C and carries out pre-nitration reaction 5h, the wherein HNO in reaction solution A3With in reaction raw materials B
The mol ratio of 6-hydroxy niacin is 1.0:1；
D () is by the concentrated sulfuric acid and red fuming nitric acid (RFNA) (mass fraction of the concentrated sulfuric acid used is 68%, and the mass fraction of red fuming nitric acid (RFNA) is 86%)
1:5 in molar ratio mix, be subsequently adding catalyst sulfuric acid hydrogen ammonium and be uniformly mixing to obtain reaction solution C, wherein red fuming nitric acid (RFNA)
Mol ratio with catalyst is 90:1；
E the pre-nitration reaction in () step (c) terminates after, the reaction solution that will obtain in step (d) under conditions of stirring
C is added dropwise in the reaction bulb in step (c), is heated to 75 DEG C and carries out nitration reaction 14h, obtains nitration reaction liquid；
F the nitration reaction liquid obtaining in step (e) is placed in 4 DEG C and carries out crystallizing 26h by (), the solids that suction filtration obtains after separating
For thick product first.
The process for separation and purification of the nitration reaction liquid of above-mentioned a kind of 6-hydroxyl-5-nitronicotinic acid, the steps include:
(1) it by the thick product first obtaining in cold methanol (2 DEG C) rinsing above-mentioned steps (f), is then vacuum dried, is slightly produced
Product second；
(2) by the thick product second obtaining in acidic aqueous solution dissolving step (2) that pH value is 1, lowering temperature crystallization is then used
Carrying out isolated and purified, cooling rate is 1 DEG C/min, and crystallization temperature is 4 DEG C, and crystallization time is 14h, finally obtains product 6-
Hydroxyl-5-nitronicotinic acid.
In the present embodiment, the productivity of 6-hydroxyl-5-nitronicotinic acid is 89.03%, and conversion ratio is 94.16%, in the present embodiment
After isolation and purification method is isolated and purified, after testing, the purity of product 6-hydroxyl-5-nitronicotinic acid is 99.16%.
Embodiment 3
The synthetic method of a kind of 6-hydroxyl-5-nitronicotinic acid, the steps include:
A () is sequentially added into the concentrated sulfuric acid and red fuming nitric acid (RFNA) in reaction bulb, stir, and obtains reaction solution A, wherein the concentrated sulfuric acid with
The mol ratio of red fuming nitric acid (RFNA) is 1:7, and the mass fraction of the concentrated sulfuric acid used is 68%, and the mass fraction of red fuming nitric acid (RFNA) is 86%；
B raw material 6-hydroxy niacin and catalyst sulfuric acid hydrogen ammonium are mixed by () according to mol ratio 70:1, obtain reaction raw materials B；
C the reaction raw materials B obtaining in step (b), under conditions of stirring, is added the reaction obtaining in step (a) molten by ()
Liquid A, is then heated to 65 DEG C and carries out pre-nitration reaction 4.5h, the wherein HNO in reaction solution A3With in reaction raw materials B
The mol ratio of 6-hydroxy niacin be 1.3:1；
D () presses the concentrated sulfuric acid and red fuming nitric acid (RFNA) (mass fraction of the concentrated sulfuric acid is 68%, and the mass fraction of red fuming nitric acid (RFNA) is 86%)
Mol ratio 1:7 mixes, and is subsequently adding catalyst sulfuric acid hydrogen ammonium and is uniformly mixing to obtain reaction solution C, wherein red fuming nitric acid (RFNA) with urge
The mol ratio of agent is 100:1；
E the pre-nitration reaction in () step (c) terminates after, the reaction solution that will obtain in step (d) under conditions of stirring
C is added dropwise in the reaction bulb in step (c), is heated to 85 DEG C and carries out nitration reaction 10h, obtains nitration reaction liquid；
F the nitration reaction liquid obtaining in step (e) is placed in 2 DEG C and carries out crystallizing 20h by (), the solids that suction filtration obtains after separating
For thick product first.
The process for separation and purification of the nitration reaction liquid of above-mentioned a kind of 6-hydroxyl-5-nitronicotinic acid, the steps include:
(1) it by the thick product first obtaining in cold methanol (0 DEG C) rinsing above-mentioned steps (f), is then vacuum dried, is slightly produced
Product second；
(2) by the thick product second obtaining in acidic aqueous solution dissolving step (2) that pH value is 2, lowering temperature crystallization is then used
Carrying out isolated and purified, cooling rate is 1 DEG C/min, and crystallization temperature is 2 DEG C, and crystallization time is 10h, finally obtains product 6-
Hydroxyl-5-nitronicotinic acid.
In the present embodiment, the productivity of 6-hydroxyl-5-nitronicotinic acid is 87.33%, and conversion ratio is 95.1%, dividing in the present embodiment
After purification process is isolated and purified, after testing, the purity of product 6-hydroxyl-5-nitronicotinic acid is 99.21%.
Claims (7)
1. a synthetic method for 6-hydroxyl-5-nitronicotinic acid, the steps include:
A () is sequentially added into the concentrated sulfuric acid and red fuming nitric acid (RFNA) in reaction bulb, stir, and obtains reaction solution A, wherein the concentrated sulfuric acid with
The mol ratio of red fuming nitric acid (RFNA) is 1:(5-7)；
(b) by raw material 6-hydroxy niacin and catalyst sulfuric acid hydrogen ammonium according to mol ratio (50-70): 1 mixes, and is reacted
Raw material B；
C the reaction raw materials B obtaining in step (b), under conditions of stirring, is added the reaction obtaining in step (a) molten by ()
In liquid A, be then heated to 50-65 DEG C and carry out pre-nitration reaction, wherein the red fuming nitric acid (RFNA) in reaction solution A with in reaction raw materials B
6-hydroxy niacin mol ratio be (1.0-1.5): 1；
D () is by the 1:(5-7 in molar ratio of the concentrated sulfuric acid and red fuming nitric acid (RFNA)) mix, it is subsequently adding the stirring of catalyst sulfuric acid hydrogen ammonium
Uniformly obtaining reaction solution C, wherein red fuming nitric acid (RFNA) and the mol ratio of catalyst are (80-100): 1；
E the pre-nitration reaction in () step (c) terminates after, the reaction solution that will obtain in step (d) under conditions of stirring
C is added dropwise in the reaction bulb in step (c), is heated to 75-85 DEG C and carries out nitration reaction, obtains nitration reaction liquid；
F () carries out under the conditions of the nitration reaction liquid obtaining in step (e) is placed in 0-4 DEG C crystallizing 20-26h, after suction filtration separates
The solids obtaining is thick product first.
2. the synthetic method of a kind of 6-hydroxyl-5-nitronicotinic acid according to claim 1, it is characterised in that: described step
A in (), the concentrated sulfuric acid and the mol ratio of red fuming nitric acid (RFNA) are 1:6.
3. the synthetic method of a kind of 6-hydroxyl-5-nitronicotinic acid according to claim 1, it is characterised in that: described step
C in (), pre-nitration reaction temperature is 60 DEG C, the reaction time is 4-5h.
4. the synthetic method of a kind of 6-hydroxyl-5-nitronicotinic acid according to claim 1, it is characterised in that: described step
E in (), nitration reaction temperature is 80 DEG C, the reaction time is 10-14h.
5. the synthetic method of a kind of 6-hydroxyl-5-nitronicotinic acid according to claim 1, it is characterised in that: described step (f)
In the separating-purifying step of thick product first be:
(1) the thick product first obtaining in the step (f) by cold methanol rinsing claim 1, is then vacuum dried, and obtains thick
Product second；
(2) by the thick product second obtaining in acidic aqueous solution dissolving step (1), then carry out isolated and purified with lowering temperature crystallization,
Crystallization temperature is 0-4 DEG C, finally obtains product 6-hydroxyl-5-nitronicotinic acid.
6. the synthetic method of a kind of 6-hydroxyl-5-nitronicotinic acid according to claim 5, it is characterised in that: described step
(2) in, the pH value of acidic aqueous solution is 1-4.
7. the synthetic method of a kind of 6-hydroxyl-5-nitronicotinic acid according to claim 5, it is characterised in that: described step
(2) in, cooling rate is 1 DEG C/min, and crystallization time is 10-14h.
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