CN104447522A - Preparation method of 5-nitro-2-aminopyridine - Google Patents
Preparation method of 5-nitro-2-aminopyridine Download PDFInfo
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- CN104447522A CN104447522A CN201410604455.4A CN201410604455A CN104447522A CN 104447522 A CN104447522 A CN 104447522A CN 201410604455 A CN201410604455 A CN 201410604455A CN 104447522 A CN104447522 A CN 104447522A
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- 0 *Nc1ncccc1[N+]([O-])=O Chemical compound *Nc1ncccc1[N+]([O-])=O 0.000 description 1
- UGSBCCAHDVCHGI-UHFFFAOYSA-N Nc(cc1)ncc1[N+]([O-])=O Chemical compound Nc(cc1)ncc1[N+]([O-])=O UGSBCCAHDVCHGI-UHFFFAOYSA-N 0.000 description 1
- ICSNLGPSRYBMBD-UHFFFAOYSA-N Nc1ncccc1 Chemical compound Nc1ncccc1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 1
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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
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- C07D213/73—Unsubstituted amino or imino radicals
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Abstract
The invention discloses a preparation method of 5-nitro-2-aminopyridine. The preparation method comprises the following steps: S1, preparing a reaction liquid I, namely adding an organic solvent to a 2-aminopyridine solution and mixing to obtain the reaction liquid I; S2, preparing a reaction liquid II, namely mixing concentrated nitric acid and concentrated sulfuric acid to obtain the reaction liquid II; and S3, preparing 5-nitro-2-aminopyridine, namely by virtue of two pumps, respectively pumping the reaction liquid I and the reaction liquid II into a microreactor, heating to 20-60 DEG C, after the reaction is completed at atmospheric pressure, separating and purifying to obtain a yellow solid 5-nitro-2-aminopyridine. Compared with the traditional preparation method, the preparation method disclosed by the invention has the advantages of simple reaction process, short reaction time, high yield, high safety, low cost, environmental friendliness and the like.
Description
Technical field
The invention belongs to medical art, be specifically related to the preparation method of 5-nitro-PA.
Background technology
5-nitro-PA is the important starting raw material of the fluoro-PA of synthesis 5-.The fluoro-PA of 5-use on medicine, biology, physics, agricultural chemicals is very extensive, can synthesize multiple enzyme, polypeptide, hormone inhibitors, antagonist etc.
The fluoro-PA of 5-is the main intermediate of novel fluoroquinolone antibiotics DW-116, and this medicine is mainly used in urinary tract infections caused by sensitive organism, gonorrhoea, prostatitis, intestinal tract infections and typhoid fever and other Salmonella infections.Be characterized in that anti-microbial effect is powerful, long half time, antimicrobial spectrum is comparatively wide, all effective to the most epistasis bacterium of gram-negative, gram-positive microorganism, mycoplasma, chlamydozoan.Therefore, fluoroquinolones is the prostatitic first-selected microbiotic for the treatment of.
The fluoro-PA of 5-is the intermediate of AMPA derivative.Multinomial research shows, in reinforcement, ampa receptor as a kind of methods for the treatment of of cognitive disorder, schizophrenia, dysthymia disorders, Parkinson's disease etc., can be among development at present.Structural formula (wherein Cl is replaced by F and obtains) is as follows:
The fluoro-PA of 5-is the key intermediate of the de-peptide deformylase inhibitors LBM-415 of synthesis.De-peptide formylase (PDF) is one of enzyme in Bacterioprotein biosynthesis process; extensively exist in prokaryotic organism; its growth, metabolism, the indispensable key enzyme of breeding; but do not contain this enzyme in the mankind and other mammalian cell, be thus regarded as a kind of comparatively ideal antimicrobial agents action target spot.The fluoro-PA of 5-is the key intermediate of the de-peptide deformylase inhibitors LBM-415 of synthesis; LBM-415 shows extremely strong inhibition to de-peptide formylase (PDF); show good anti-microbial activity in human body simultaneously; namely there is broad-spectrum antibacterial action; the indices of its Internal pharmacokinetics and pharmacodynamics is all good; and can not produce with other microbiotic and interact, be a kind of antibacterials with development prospect.
The fluoro-PA of 5-can also as the intermediate of the antagonist of the inhibitor of aspartic acid specificity cysteine protease caspases-3, chemokine ccr 5,5-HT receptor antagonist etc.
The Complex Crystal (5FAP) that the fluoro-PA of 5-and cupric chloride, hydrochloric acid reaction generate
2cuCl
4due to the crystalline structure that it is special, and have significant magnetic interaction, monocrystalline and powder susceptibility data show this kind of low-dimensional crystal and have very strong diamagnetism matter, this just high temperature superconducting materia can produce the key point of supraconductivity, structural formula is as follows:
The fluoro-PA of 5-is the intermediate of the fluoro-2-amino of pesticide intermediate 5--3-nitropyridine.Fluorine-containing pyridine farm chemical has high-efficiency low-toxicity, low residue, environment amenable feature, is widely used.5-fluoro-2-amino-3-nitropyridine structural formula is as follows:
Make a general survey of the document both at home and abroad preparation of 5-nitro-PA reported little, and it is a lot of to 5-fluoro-PA preparation research report, but in these reports, the preparation of 5-nitro-PA is just briefly touched upon, all with traditional still reaction, most yield, less than 60%, carries out process optimization to it not separately.One section of " preparation of 3-nitro-PA and 5-nitro-PA " (chemical reagent by name, 2005,27 (5), method is mentioned: PA is dissolved in the vitriol oil in report 309-310), drip the nitration mixture of the vitriol oil and dense nitre sulphur, nitration reaction temperature is controlled within 30 DEG C, reaction 2h, reset with the vitriol oil again after water isolation of intermediate products on the rocks, 50 DEG C of reaction 5h, add frozen water, separated product, then use wet distillation segregation ratio subliming method purified product.Reaction formula is:
This method reaction yield is higher, and yield is 63.7%.This nitration reaction has certain delayed, and reaction, once cause, is released a large amount of heat, during still reaction, easily rushed material, there is huge potential safety hazard; And this method is reacted, purification process is loaded down with trivial details, long reaction time, energy consumption is high, and environment is unfriendly, is not suitable for large-scale commercial production.
Summary of the invention
The object of the invention is to the shortcoming overcoming prior art, provide the preparation method of 5-nitro-PA.The method thoroughly solves classical inverse and answers long reaction time in production model, and efficiency is low, and mix uneven, foreign matter content is high, uppity problem; Have simple to operate, cost is low, less energy consumption, yield are high, purity is high, security is high, the content of by product C is low, without iodine, the advantages such as steady quality.
Object of the present invention is achieved through the following technical solutions: the preparation method of 5-nitro-PA, and the reaction equation that described preparation method relates to is:
Apply the preparation method of the 5-nitro-PA of above-mentioned reaction, it comprises the following steps:
S1. reaction solution I is prepared: add organic solvent to PA solution and be mixed to get reaction solution I;
S2. reaction solution II is prepared: concentrated nitric acid, the vitriol oil are mixed to get reaction solution II;
S3. prepare 5-nitro-PA: use two pumps, add in microreactor respectively, be heated to 20 ~ 60 DEG C by reaction solution I, reaction solution II, after synthesis under normal pressure is complete, namely separation and purification obtains 5-nitro-PA.
Further, the solution usage of PA described in step S1 is 100 ~ 300g, organic solvent is 200 ~ 900mL, wherein, organic solvent comprises methyl alcohol, ethanol, Virahol, propyl carbinol, propyl alcohol, isopropylcarbinol, the trimethyl carbinol, ethyl acetate, tetrahydrofuran (THF), methylene dichloride, ethylene dichloride, chloroform, toluene, dimethylbenzene, methyl-sulphoxide, N, one in dinethylformamide, sherwood oil or their mixed solvents, the one in preferred ethylene dichloride, methylene dichloride or mixed solvent.
The massfraction of nitric acid described in step S2 is 65%, and sulfuric acid massfraction is 98%, and presses the mass ratio mixing of 1:5 ~ 9.
Pump described in step S3 comprises ram pump, surge pump, syringe pump and peristaltic pump.
The flow velocity of reaction solution I described in step S3 selects 40 ~ 60mL/min, is preferably 50mL/min; The flow velocity of reaction solution II is determined according to the amount of reaction solution I, and the equivalence ratio keeping 2-amido pyridine and nitric acid is 1.1.
Reactor described in step S3 is microchannel flow reactor.
Temperature of reaction described in step S3 is 20 ~ 60 DEG C, preferably 35 ~ 45 DEG C, and optimum is 35 DEG C.
The process of separation and purification described in step S3 comprises adjust ph, cooling, crystallization, filtration, chemical separation and drying, wherein the adjustment of pH be to collect reaction solution I, reaction solution II product in slowly add 25% ~ 28% ammoniacal liquor, pH reaches 8; It is liquid is cooled to 0 DEG C of crystallization to filter that crystallisation by cooling filters; Chemical separation is added to the water filtering the solid obtained, add the hydrochloric acid of 0.9 equivalent 36%, backflow 2h, be cooled to 0 DEG C of crystallization, obtain 5-nitro-PA HCl, solid, then be that 20% sodium hydroxide solution regulates pH to be 8 with massfraction, filter, 50 DEG C of vacuum-dryings, the solid obtained is 5-nitro-PA.
The preparation method of 5-nitro-PA of the present invention, use microreactor (microchannel flow reactor) to substitute traditional reactor, its floor space is little, only 2 square metres, uninterrupted production continuously in 24 hours can be realized, without scale effect, mix, reproducible; Temperature, pressure are easy to control, and to heat release, stronger reaction of absorbing heat, advantage is more obvious, and safety coefficient is high.
The following advantage that the preparation method of 5-nitro-PA of the present invention has: (1) reaction yield is high, and raw material availability is high, and solvent can reuse, and cost significantly reduces; (2) method is simple to operation, production process safety, and speed of response, temperature are easy to control; (3) production capacity is high, and flow reactor does not have scale effect, mixes, reproducible; (4) three wastes are few, belong to typical friendly process.
Embodiment
Below in conjunction with embodiment, the present invention will be further described, and protection scope of the present invention is not limited to the following stated.
The HPLC of 5-nitro of the present invention-PA test is as follows:
Model: Agilent 1100; Detector: G1321A; Chromatographic column: Gemini C18,4.0x250mm; Moving phase: 0.1TFA/H2O:MeCN=70:30; Column temperature: 25 DEG C; Flow velocity: 1mL/min; Product retention time: 4.96min.
Production capacity described in the present invention is the time ratio that the product weight prepared completes with reaction solution charging.Reaction yield of the present invention is the product weight of real income and the ratio of theoretical yield.
The preparation method of embodiment 1:5-nitro-PA, it comprises the steps:
1) reaction solution I is prepared: get PA (100g, 1.06mol) and add in 1L four-hole boiling flask, temperature control 23 DEG C, add 250mL ethylene dichloride, stir, wait after dissolving completely, add ethylene dichloride constant volume to 353mL, the volumetric molar concentration of PA is 3mol/L;
2) preparation feedback liquid II: 65% concentrated nitric acid (125g, 1.29mol) is added in 1L four-hole bottle, water-bath temperature control, slow dropping 98% vitriol oil (625g, 6.96mol), having configured rear liquor capacity is 540mL, and the volumetric molar concentration of nitric acid content is 2.39mol/L;
3) 5-nitro-PA is prepared: temperature of reactor is raised to 35 DEG C, pressure is set to 0MPa, use two pumps, add in microreactor by reaction solution I, reaction solution II, reaction solution I flow rate set is 40mL/min, reaction solution II is added by 1.1 equivalents, i.e. flow rate set 36mL/min, after 30s, reaction solution flows out microreactor, be collected in container for storing liquid, continue to be fed to and run out of all materials;
Reaction equation is:
Reaction solution sampling HPLC analyzes, product B content 78.6%, by product C content 20.1%.
Separation and purification: reaction solution frozen water is lowered the temperature, and slowly add the ammoniacal liquor of 26%, regulate pH=8, continue to be cooled to 0 DEG C, separate out a large amount of grass green solid, filter, solid is dissolved in 200mL water, adds 36% hydrochloric acid (70g, 0.7mol) of 0.9 equivalent, reflux 2h, be cooled to 0 DEG C of crystallization, filter, obtain 5-nitro-PA and obtain HCl, solid, pH=8 is regulated with 20% sodium hydroxide solution, filter, 50 DEG C of vacuum-dryings, obtain yellow solid 5-nitro-PA 113.61g, purity 99.43%, yield is 76.49%.1HNMR:6.48(S,1H),7.52(S,2H),8.12(S,1H)，8.83(S,1H)。
The preparation method of embodiment 2:5-nitro-PA, it comprises the steps:
1) reaction solution I is prepared: get PA (200g, 2.13mol) and add in 1L four-hole boiling flask, temperature control 23 DEG C, add 550mL ethylene dichloride, stir, wait after dissolving completely, add ethylene dichloride constant volume to 706mL, the volumetric molar concentration of PA is 3mol/L.
2) preparation feedback liquid II: 65% concentrated nitric acid (250g, 2.58mol) is added in 2L four-hole bottle, water-bath temperature control, slow dropping 98% vitriol oil (1750g, 19.50mol), configured rear solution 1080mL, the volumetric molar concentration of nitric acid is 2.39mol/L.
3) 5-nitro-PA is prepared: temperature of reactor is raised to 40 DEG C, pressure is set to 0MPa, use two pumps, add in microreactor by reaction solution I, reaction solution II, reaction solution I flow rate set is 50mL/min, reaction solution II is added by 1.1 equivalents, flow rate set 46mL/min, after 30s, reaction solution flows out microreactor, be collected in container for storing liquid, continue to be fed to and run out of all materials.
Reaction equation is:
Sampling HPLC analyzes, product B content 77.3%, by product C content 20.5%.
Separation and purification: reaction solution frozen water is lowered the temperature, and slowly add the ammoniacal liquor of 26%, regulate pH=8, continue to be cooled to 0 DEG C, separate out a large amount of grass green solid, filter, solid is dissolved in 400mL water, adds 36% hydrochloric acid (140g, 1.4mol) of 0.9 equivalent, reflux 2h, be cooled to 0 DEG C of crystallization, filter, obtain 5-nitro-PA and obtain HCl, solid, be 8 by 20% sodium hydroxide solution adjust ph, filter, 50 DEG C of vacuum-dryings, obtain yellow solid 5-nitro-PA 227.43g, purity 99.11%, yield is 76.21%.1HNMR:6.53(S,1H),7.59(S,2H),8.17(S,1H)，8.81(S,1H)。
The preparation method of embodiment 3:5-nitro-PA, it comprises the steps:
1) reaction solution I is prepared: get PA (300g, 3.19mol) and add in 1L four-hole boiling flask, temperature control 23 DEG C, add 900mL ethylene dichloride, stir, wait after dissolving completely, add ethylene dichloride constant volume to 1600mL, the volumetric molar concentration of PA is 2mol/L.
2) preparation feedback liquid II: 65% concentrated nitric acid (351g, 3.51mol) is added in 1L four-hole bottle, water-bath temperature control, slow dropping 98% vitriol oil (3159g, 35.2mol), configured rear solution 1468mL, the volumetric molar concentration of nitric acid content is 2.39mol/L.
3) 5-nitro-PA is prepared: temperature of reactor is raised to 45 DEG C, pressure is set to 0MPa, use two pumps, add in microreactor by reaction solution I, reaction solution II, reaction solution I flow rate set is 60mL/min, reaction solution II is added by 1.1 equivalents, flow rate set 55mL/min, after 30s, reaction solution flows out microreactor, be collected in container for storing liquid, continue to be fed to and run out of all materials.
Reaction equation is:
Sampling HPLC analyzes, product B content 77.9%, by product C content 20.6%.
Separation and purification: reaction solution frozen water is lowered the temperature, and slowly add the ammoniacal liquor of 26%, regulate pH=8, continue to be cooled to 0 DEG C, separate out a large amount of grass green solid, filter, solid is dissolved in 600mL water, adds 36% hydrochloric acid (226.2g, 2.2mol) of 0.9 equivalent, reflux 2h, be cooled to 0 DEG C of crystallization, filter, obtain 5-nitro-PA and obtain HCl, solid, pH=8 is regulated with 20% sodium hydroxide solution, filter, 50 DEG C of vacuum-dryings, obtain yellow solid 5-nitro-PA 340.03g, purity 99.39%, yield is 76.32%.1HNMR:6.46(S,1H),7.53(S,2H),8.13(S,1H)，8.81(S,1H)。
The preparation method of embodiment 4:5-nitro-PA, it comprises the steps:
1) reaction solution I is prepared: get PA (300g, 3.19mol) and add in 1L four-hole boiling flask, temperature control 23 DEG C, add 900mL methylene dichloride, stir, wait after dissolving completely, add methylene dichloride constant volume to 1600mL, the volumetric molar concentration of PA is 2mol/L.
2) preparation feedback liquid II: 65% concentrated nitric acid (351g, 3.51mol) is added in 1L four-hole bottle, water-bath temperature control, slow dropping 98% vitriol oil (2457g, 24.57mol), configured rear solution 1468mL, the volumetric molar concentration of nitric acid is 2.39mol/L.
3) 5-nitro-PA is prepared: temperature of reactor is raised to 35 DEG C, pressure is set to 0MPa, use two pumps, add in microreactor by reaction solution I, reaction solution II, reaction solution I flow rate set is 60mL/min, reaction solution II is added by 1.1 equivalents, flow rate set 46mL/min, after 35s, reaction solution flows out microreactor, be collected in container for storing liquid, continue to be fed to and run out of all materials.
Reaction equation is:
Sampling HPLC analyzes, product B content 80.9%, by product C content 18.4%.
Separation and purification: reaction solution frozen water is lowered the temperature, and slowly add the ammoniacal liquor of 28%, regulate pH=8, continue to be cooled to 0 DEG C, separate out a large amount of grass green solid, filter, solid is dissolved in 600mL water, add 36% hydrochloric acid (234.9g of 0.9 equivalent, 2.32mol), reflux 80 DEG C of 3h, be cooled to zero DEG C of crystallization, filter, obtain 5-nitro-PA and obtain HCl, solid, be 8 by 20% sodium hydroxide solution adjust ph, filter, normal temperature infrared is dry, obtain yellow solid 5-nitro-PA 351.75g, purity 99.49%, yield is 78.95%.1HNMR:6.39(S,1H),7.52(S,2H),8.10(S,1H)，8.73(S,1H)。
The preparation method of embodiment 5:5-nitro-PA, it comprises the steps:
1) reaction solution I is prepared: get PA (300g, 3.19mol) and add in 1L four-hole boiling flask, temperature control 23 DEG C, add 900mL methyl alcohol, stir, wait after dissolving completely, add methanol constant volume to 1600mL, the volumetric molar concentration of PA is 2mol/L.
2) preparation feedback liquid II: 65% concentrated nitric acid (351g, 3.51mol) is added in 1L four-hole bottle, water-bath temperature control, slow dropping 98% vitriol oil (2457g, 24.57mol), configured rear solution 1468mL, the volumetric molar concentration of nitric acid is 2.39mol/L.
3) 5-nitro-PA is prepared: temperature of reactor is raised to 20 DEG C, pressure is set to 0MPa, use two pumps, add in microreactor by reaction solution I, reaction solution II, reaction solution I flow rate set is 50mL/min, reaction solution II is added by 1.1 equivalents, flow rate set 46mL/min, after 35s, reaction solution flows out microreactor, be collected in container for storing liquid, continue to be fed to and run out of all materials.
Reaction equation is:
Separation and purification: reaction solution frozen water is lowered the temperature, and slowly add the ammoniacal liquor of 28%, regulate pH=8, continue to be cooled to 0 DEG C, separate out a large amount of grass green solid, filter, solid is dissolved in 600mL water, add 36% hydrochloric acid (234.9g of 0.9 equivalent, 2.32mol), reflux 80 DEG C of 3h, are cooled to zero DEG C of crystallization, filter, obtaining 5-nitro-PA and obtain HCl, solid, is 8 by 20% sodium hydroxide solution adjust ph, filters, normal temperature infrared is dry, and obtaining yellow solid 5-nitro-PA yield is 54.31%.
The preparation method of embodiment 6:5-nitro-PA, it comprises the steps:
1) reaction solution I is prepared: get PA (300g, 3.19mol) add in 1L four-hole boiling flask, temperature control 23 DEG C, add the mixed solvent of 900mL methylene dichloride and ethylene dichloride (volume ratio 1:1), stir, after dissolving completely, add mixed solvent constant volume to 1600mL, the volumetric molar concentration of PA is 2mol/L.
2) preparation feedback liquid II: 65% concentrated nitric acid (351g, 3.51mol) is added in 1L four-hole bottle, water-bath temperature control, slow dropping 98% vitriol oil (2457g, 24.57mol), configured rear solution 1468mL, the volumetric molar concentration of nitric acid is 2.39mol/L.
3) 5-nitro-PA is prepared: temperature of reactor is raised to 35 DEG C, pressure is set to 0MPa, use two pumps, add in microreactor by reaction solution I, reaction solution II, reaction solution I flow rate set is 60mL/min, reaction solution II is added by 1.1 equivalents, flow rate set 55mL/min, after 35s, reaction solution flows out microreactor, be collected in container for storing liquid, continue to be fed to and run out of all materials.
Reaction equation is:
Separation and purification: reaction solution frozen water is lowered the temperature, and slowly add the ammoniacal liquor of 28%, regulate pH=8, continue to be cooled to 0 DEG C, separate out a large amount of grass green solid, filter, solid is dissolved in 600mL water, add 36% hydrochloric acid (234.9g of 0.9 equivalent, 2.32mol), reflux 80 DEG C of 3h, are cooled to zero DEG C of crystallization, filter, obtaining 5-nitro-PA and obtain HCl, solid, is 8 by 20% sodium hydroxide solution adjust ph, filters, normal temperature infrared is dry, and obtaining yellow solid 5-nitro-PA yield is 77.89%.
The preparation method of embodiment 7:5-nitro-PA, it comprises the steps:
1) reaction solution I is prepared: get PA (300g, 3.19mol) and add in 1L four-hole boiling flask, temperature control 23 DEG C, add 900mL toluene, stir, wait after dissolving completely, add toluene constant volume to 1600mL, the volumetric molar concentration of PA is 2mol/L.
2) preparation feedback liquid II: 65% concentrated nitric acid (351g, 3.51mol) is added in 1L four-hole bottle, water-bath temperature control, slow dropping 98% vitriol oil (2457g, 24.57mol), configured rear solution 1468mL, the volumetric molar concentration of nitric acid is 2.39mol/L.
3) 5-nitro-PA is prepared: temperature of reactor is raised to 45 DEG C, pressure is set to 0MPa, use two pumps, add in microreactor by reaction solution I, reaction solution II, reaction solution I flow rate set is 40mL/min, reaction solution II is added by 1.1 equivalents, flow rate set 36mL/min, after 35s, reaction solution flows out microreactor, be collected in container for storing liquid, continue to be fed to and run out of all materials.
Reaction equation is:
Separation and purification: reaction solution frozen water is lowered the temperature, and slowly add the ammoniacal liquor of 28%, regulate pH=8, continue to be cooled to 0 DEG C, separate out a large amount of grass green solid, filter, solid is dissolved in 600mL water, add 36% hydrochloric acid (234.9g of 0.9 equivalent, 2.32mol), reflux 80 DEG C of 3h, are cooled to zero DEG C of crystallization, filter, obtaining 5-nitro-PA and obtain HCl, solid, is 8 by 20% sodium hydroxide solution adjust ph, filters, normal temperature infrared is dry, and obtaining yellow solid 5-nitro-PA yield is 70.39%.
Below by way of description of test beneficial effect of the present invention:
Use the preparation method of traditional 5-nitro-PA to test, contrast.
Comparison example 1: the preparation method of traditional 5-nitro-PA, it comprises the steps:
Get the 13mL98% vitriol oil and put into 100mL there-necked flask, water-bath temperature control, slowly add 6g2-aminopyridine, control temperature, lower than 30 DEG C, then slowly drips nitration mixture (the 5mL98% vitriol oil and 6mL65% concentrated nitric acid), after being added dropwise to complete, stirs 2h.Reaction solution is added in frozen water, filter, obtain yellow solid 7.52g.
Again above-mentioned solid is added in the 70mL98% vitriol oil, be heated to 50 DEG C, after reaction 5h, then reaction solution is poured in frozen water, filter, obtain yellow solid 6.32g.
Separation and purification: 6.32g solid is added 40mL water, underpressure distillation, obtains 5-nitro-PA 5.15g.
Test: mass spectrum: MS (M+H+): m/z140.1.
Nucleus magnetic resonance: 1HNMR:6.44 (S, 1H), 7.43 (S, 2H), 8.01 (S, 1H), 8.52 (S, 1H).
HPLC: purity 95.42%.
Yield: theoretical yield is 8.94g, actual output is 5.15g, and yield is 57.61%.
Comparison example 2: the preparation method of traditional 5-nitro-PA, it comprises the steps:
Get the 80mL98% vitriol oil and put into 100mL there-necked flask, water-bath temperature control, slowly add 10g2-aminopyridine, control temperature, lower than 35 DEG C, then slowly drips 11.34g65% nitric acid, after being added dropwise to complete, is warming up to 45 DEG C, stirs 2h.HPLC tests, product assay 66%.
Separation and purification: reaction solution frozen water is lowered the temperature, and slowly add the ammoniacal liquor of 25%-28%, regulate pH=8, continue to be cooled to 0 DEG C, separate out a large amount of grass green solid, filter, solid is dissolved in 20mL water, adds the hydrochloric acid (7g, 0.07mol) of 36%, reflux 1h, decrease temperature crystalline, filters, obtain 5-nitro-PA and obtain HCl, solid, separate salt with 20% sodium hydroxide solution 15g, filter, drying, obtains yellow solid 5-nitro-PA 8.33g.
Test: mass spectrum: MS (M+H+): m/z140.1.
Nucleus magnetic resonance: 1HNMR:6.55 (S, 1H), 7.61 (S, 2H), 8.19 (S, 1H), 8.85 (S, 1H).
HPLC: purity 98.19%.
Yield: theoretical yield is 14.85g, actual output is 8.33g, and yield is 56.09%.
Compared with comparison example 1 ~ 2 from embodiment 1 ~ 7: for traditional 5-nitro-PA preparation method, preparation method's yield of the present invention is high, and the reaction times is short, and temperature is more easy to control, reaction process safe and continuous, can realize scale operation.
Claims (10)
- The preparation method of 1.5-nitro-PA, it is characterized in that, it comprises the following steps:S1. reaction solution I is prepared: add organic solvent to PA solution and be mixed to get reaction solution I;S2. reaction solution II is prepared: concentrated nitric acid, the vitriol oil are mixed to get reaction solution II;S3. prepare 5-nitro-PA: use two pumps, add in microreactor respectively, be heated to 20 ~ 60 DEG C by reaction solution I, reaction solution II, after synthesis under normal pressure is complete, namely separation and purification obtains 5-nitro-PA.
- 2. the preparation method of 5-nitro-PA according to claim 1, it is characterized in that, it comprises the following steps:S1. reaction solution I is prepared: PA solution 100 ~ 300g, adds organic solvent 200 ~ 900mL wherein, obtains reaction solution I;S2. preparation reaction solution II: 65% concentrated nitric acid and 98% vitriol oil press the mass ratio mixing of 1:5 ~ 9, obtain reaction solution II;S3. 5-nitro-PA is prepared: use two pumps, with the flow velocity of 1 ~ 200mL/min, reaction solution I, reaction solution II are added in continous way microreactor respectively, be heated to 20 ~ 60 DEG C, after synthesis under normal pressure is complete, separation and purification obtains decorating film, i.e. 5-nitro-PA.
- 3. the preparation method of 5-nitro-PA according to claim 1 and 2, it is characterized in that, described organic solvent comprises a kind of in methyl alcohol, ethanol, Virahol, propyl carbinol, water, propyl alcohol, isopropylcarbinol, the trimethyl carbinol, acetone, ethyl acetate, tetrahydrofuran (THF), methylene dichloride, ethylene dichloride, chloroform, toluene, dimethylbenzene, methyl-sulphoxide, DMF, sherwood oil or their mixed solvent.
- 4. the preparation method of 5-nitro-PA according to claim 1 and 2, it is characterized in that, described pump comprises ram pump, surge pump, syringe pump and peristaltic pump.
- 5. the preparation method of 5-nitro-PA according to claim 1 and 2, it is characterized in that, reaction solution I adds in microreactor with the flow velocity of 40 ~ 60mL/min by described pump, the flow velocity of reaction solution II is determined according to the amount of reaction solution I, and the equivalence ratio keeping 2-amido pyridine and nitric acid is 1.1.
- 6. the preparation method of 5-nitro-PA according to claim 1 and 2, is characterized in that, described temperature of reaction is 35 ~ 45 DEG C.
- 7. the preparation method of 5-nitro-PA according to claim 1 and 2, it is characterized in that, described separation and purification comprises adjust ph, cooling, crystallization, filtration, chemical separation and drying step.
- 8. the preparation method of 5-nitro-PA according to claim 7, it is characterized in that, described pH value regulate detailed process be slowly add in the reaction solution collected 25% ~ 28% ammoniacal liquor, regulate pH to be 8, described reaction solution is the product of reaction solution I, reaction solution II.
- 9. the preparation method of 5-nitro-PA according to claim 7, it is characterized in that, described cooling, crystallization, filtration detailed process be by adjust ph after liquid cool to 0 DEG C of crystallization, refilter, obtain solid fraction intermediate, described liquid refers to the product of reaction solution I, reaction solution II.
- 10. the preparation method of 5-nitro-PA according to claim 7, it is characterized in that, described chemical separation is dissolved in water by the intermediate filtered, add the hydrochloric acid of 36% of 0.9 equivalent, heat 80 DEG C of backflow 2h, be cooled to 0 DEG C of crystallization, filter to obtain 5-nitro-PA HCl, solid, gained solid dispersal is in 4 times of weight water, be 8 by the sodium hydroxide solution adjust ph that massfraction is 20%, filter, 50 DEG C of vacuum-dryings, obtain solid 5-nitro-PA.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105523995A (en) * | 2015-12-17 | 2016-04-27 | 浙江汇能生物股份有限公司 | Preparation method for malaridine intermediate 2-methoxy-5-aminopyridine |
| CN116178250A (en) * | 2022-12-28 | 2023-05-30 | 山东特创新材料科技有限公司 | Method for preparing 2-amino-5-nitropyridine by utilizing microchannel reactor |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100298567A1 (en) * | 2006-01-12 | 2010-11-25 | Lonza Ag | Nitration of activated aromatics in microreactors |
| CN102040554A (en) * | 2010-12-06 | 2011-05-04 | 张家港任发化工材料有限公司 | Method for preparing 2-chloro-5-nitropyridine |
| CN102796039A (en) * | 2012-08-16 | 2012-11-28 | 浙江工业大学 | Method for continuous preparation of 2-chloro-5-chloromethylpyridine in microchannel |
-
2014
- 2014-10-31 CN CN201410604455.4A patent/CN104447522B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100298567A1 (en) * | 2006-01-12 | 2010-11-25 | Lonza Ag | Nitration of activated aromatics in microreactors |
| CN102040554A (en) * | 2010-12-06 | 2011-05-04 | 张家港任发化工材料有限公司 | Method for preparing 2-chloro-5-nitropyridine |
| CN102796039A (en) * | 2012-08-16 | 2012-11-28 | 浙江工业大学 | Method for continuous preparation of 2-chloro-5-chloromethylpyridine in microchannel |
Non-Patent Citations (2)
| Title |
|---|
| 何伟等: "微反应器在合成化学中的应用", 《应用化学》 * |
| 马振萍等: "2-氨基-5-氟吡啶的合成", 《高校化学工程学报》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105523995A (en) * | 2015-12-17 | 2016-04-27 | 浙江汇能生物股份有限公司 | Preparation method for malaridine intermediate 2-methoxy-5-aminopyridine |
| CN116178250A (en) * | 2022-12-28 | 2023-05-30 | 山东特创新材料科技有限公司 | Method for preparing 2-amino-5-nitropyridine by utilizing microchannel reactor |
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Address after: Wenjiang District 611137 of Sichuan city of Chengdu province Chengdu Strait science and Technology Industry Development Park No. 488 West Ke Lin Lu Patentee after: Astatech (Chengdu) biological pharmaceutical Limited by Share Ltd Address before: Wenjiang District 611137 of Sichuan city of Chengdu province Chengdu Strait science and Technology Industry Development Park No. 488 West Ke Lin Lu Patentee before: ASTATECH (CHENGDU) PHARM. CO., LTD. |