CN102249995A - Synthetic method for preparing pyridine N-oxide - Google Patents
Synthetic method for preparing pyridine N-oxide Download PDFInfo
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- CN102249995A CN102249995A CN2011102174466A CN201110217446A CN102249995A CN 102249995 A CN102249995 A CN 102249995A CN 2011102174466 A CN2011102174466 A CN 2011102174466A CN 201110217446 A CN201110217446 A CN 201110217446A CN 102249995 A CN102249995 A CN 102249995A
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- 0 Cc1c(C)nc(*)c(*)c1* Chemical compound Cc1c(C)nc(*)c(*)c1* 0.000 description 1
- YVKVHQFORNOBTC-UHFFFAOYSA-N [O-][n+](cc(cc1)Cl)c1[ClH]I Chemical compound [O-][n+](cc(cc1)Cl)c1[ClH]I YVKVHQFORNOBTC-UHFFFAOYSA-N 0.000 description 1
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Abstract
Provided is a synthetic method for preparing pyridine N-oxide. According to the method, raw materials which are commercialized on the market are selected, or pyridine, monosubstituted pyridine or polysubstituted pyridine derivatives which are easy to prepare are used as starting materials, and the materials are oxidized by urea-hydrogen peroxide compound so to prepare the final product. The advantages of the invention are as follows: 1, the raw materials used in the invention are easily available and cheap and are commercialized or easily preparable raw materials, meeting requirements for large scale production; 2, a safer oxidation method is employed in the invention, thereby avoiding condensation of acetate containing hydrogen peroxide and greatly improving safety factors of production; 3, chemical reaction conditions required in the invention are mild, the operation is simple, little pollution to environment is produced, and the method is technically mature for large scale production.
Description
(1) technical field:
The present invention relates to a kind of synthetic method of important organic chemical industry's intermediate, particularly a kind of synthetic method for preparing pyridine nitric oxide.
(2) background technology:
The pyridines oxynitride belongs to the derivative of pyridine, and it is the important organic chemical industry's intermediate of a class, is widely used in many chemical fields such as medicine, dyestuff, catalysis.Contain that the novel agrochemical of pyridine group, medical type are various to have a very strong physiologically active.These novel agrochemicals are not only efficient, low toxicity, wide spectrum, and people and animal are had remarkable Environmental compatibility, meet the development trend of current agricultural chemicals.Aspect medical, it is Synthetic 2-chloromethyl-4-methoxyl group-3, and the important intermediate of 5-dimethyl pyrazole thiamine hydrochloride also is the important intermediate of preparation cardiotonic drug, disinfectant, anti-arrhythmic, anti-ulcerative drug etc.Pyridin-N-oxide and its derives can be used as catalyzer and is widely used in the various reactions, can also be used for dyestuffs industries as oxygenant.Therefore the research of this compounds has important theory value and actual practical value.
The method that present stage prepares this type of pyridine nitric oxide mainly contains following three classes:
1, with the pyridine compounds is main raw material, under titanium silicate catalysis, obtains through hydrogen peroxide oxidation.Though this reaction productive rate is higher, catalyzer costs an arm and a leg and is difficult for reclaiming, and the reaction times is longer, and practice is worth little.
2, with the pyridine compounds be main raw material, oxidation generates final product under hydrogen peroxide and glacial acetic acid effect.This process solvent consumption is big, and aftertreatment needs repeatedly extraction, trivial operations, and it is relatively poor to concentrate the system security that contains hydrogen peroxide for a long time, increases product and decomposes risk, is not suitable for suitability for industrialized production.
3, with the pyridine compounds be main raw material, obtain end product through the phthalic acid peroxide oxidation.Though this method has avoided using a large amount of solvents, the price of starting material own is very high and aftertreatment is difficult.
More than three class synthetic methods all have certain defective, can not satisfy present need of industrial production.Therefore for solving a difficult problem that exists in the prior art, suddenly wait the practicable synthesis technique that finds to carry out large-scale production.
(3) summary of the invention:
The object of the present invention is to provide a kind of synthetic method of more excellent pyridines oxynitride; it can overcome above-mentioned the deficiencies in the prior art; this method raw material is easy to get; reaction purity, yield is higher; stable process conditions; simple to operate, be applicable to large-scale production, for preparation pyridines oxynitride has supplied a kind of new thinking and method.
Technical scheme of the present invention: a kind of synthetic method for preparing pyridine nitric oxide is characterized in that concrete preparation process is as follows:
(1) preparation urea hydrogen peroxide mixture: hydrogen peroxide and stablizer and urea are in 0～40 ℃ of insulation reaction; Reaction is finished, and is cooled to-10～15 ℃, and is centrifugal behind insulated and stirred 0.5～3h, and filter cake obtains the urea hydrogen peroxide mixture with ester class or ether solvent drip washing;
Wherein the mol ratio of urea and hydrogen peroxide is 1: 0.5～3, and stabilizing agent dosage is every gram urea 0.001～0.1 gram, and ester class or ethers consumption are every gram urea 0.5～3.5ml;
(2) preparation
Reaction process: in the presence of ester class or nitrile solvents and acid anhydrides, add main raw material
System is warming up to 30～110 ℃, and 30～110 ℃ of temperature controls add urea hydrogen peroxide mixture insulation reaction; After reacting completely, be cooled to 0～50 ℃, add saturated reductibility reagent solution to starch potassium iodide paper and no longer become blue, adding alkaline solution regulation system pH value is 8～10 to making pH value, centrifugal, extraction, concentrated;
R wherein
1～R
5Be alkyl, the protium of replacement or polysubstituted C1～C3, hydroxyl, methoxyl group, oxyethyl group, halogen (F, Cl, Br, I); Ester class or nitrile solvents consumption are every gram main raw material
3～15mL; Main raw material
With the mol ratio of acid anhydrides be 1: 1～4; Main raw material
With urea hydrogen peroxide mixture mol ratio be 1: 1～4.5;
(3) make product: promptly obtain product
In the above-mentioned steps (1), the mol ratio of urea and hydrogen peroxide is 1: 0.5～2; Stabilizing agent dosage is every gram urea 0.001～0.05 gram, and ester class or ethers consumption are every gram urea 0.5～2.5ml.
Ester class in the above-mentioned steps (2) or nitrile solvents consumption are every gram main raw material
3～10mL; Main raw material
With the mol ratio of acid anhydrides be 1: 1～3; Main raw material
With urea hydrogen peroxide mixture mol ratio be 1: 1～3.5; The alkaline solution consumption is 9～10 for making the system pH value.
In the above-mentioned steps (1), the mol ratio of urea and hydrogen peroxide is 1: 0.5～1.5; Stabilizing agent dosage is every gram urea 0.001～0.01 gram, and ester class or ethers consumption are every gram urea 0.5～2ml.
Ester class in the above-mentioned steps (2) or nitrile solvents consumption are every gram main raw material
4～8mL; Main raw material
With the mol ratio of acid anhydrides be 1: 1～2.5; Main raw material
With urea hydrogen peroxide mixture mol ratio be 1: 1～2.5; The alkaline solution consumption is 9～10 for making the system pH value.
Stablizer in the above-mentioned steps (1) is potassium primary phosphate, Seignette salt, citric acid, Whitfield's ointment and ethylenediamine tetraacetic acid (EDTA); Ester class or ether solvent are sherwood oil, ethyl acetate, isopropyl acetate.
Ester class in the above-mentioned steps (2) or nitrile solvents are ethyl acetate, isopropyl acetate, acetonitrile; Acid anhydrides is diacetyl oxide, Tetra hydro Phthalic anhydride, maleic anhydride, Succinic anhydried; Reductibility reagent is sodium bisulfite, S-WAT, Sulfothiorine, sodium sulphite, ferrous sulfate; Alkaline solution is sodium hydroxide, potassium hydroxide, sodium bicarbonate, yellow soda ash, ammoniacal liquor.
Stablizer in the above-mentioned steps (1) is preferably citric acid, Whitfield's ointment and ethylenediamine tetraacetic acid (EDTA); Ester class or ether solvent are sherwood oil, isopropyl acetate.
Ester class in the above-mentioned steps (2) or nitrile solvents are ethyl acetate, isopropyl acetate, acetonitrile etc.; Acid anhydrides comprises diacetyl oxide, Tetra hydro Phthalic anhydride, Succinic anhydried etc.; Reductibility reagent is preferably sodium bisulfite, S-WAT, Sulfothiorine etc.; Alkaline solution is preferably sodium hydroxide, sodium bicarbonate, ammoniacal liquor etc.
Superiority of the present invention: 1, the raw material of the present invention's employing all is easy to get and low price; The raw materials used raw material that is business-like raw material or easily prepares can satisfy needs of scale production; 2, the present invention uses safer method for oxidation, has avoided concentrating the acetate that contains hydrogen peroxide, has improved the production safety coefficient greatly; 3, chemical reaction condition gentleness of the present invention, easy and simple to handle, environmental pollution is little, and the ripe ability that possesses large-scale production on this Technology.
(4) description of drawings:
Fig. 1 is the related a kind of flow chart of steps for preparing the synthetic method of pyridine nitric oxide of the present invention.
Fig. 2 is the related a kind of chemical reaction process schema for preparing the synthetic method of pyridine nitric oxide of the present invention.
Can understand the technical scheme of foregoing invention more intuitively in conjunction with Fig. 1 and/or Fig. 2.
(5) embodiment:
For the interval range that occurs in the embodiment is owing to carry out meeting appearance certain float of temperature in single test with reaction process.
Embodiment 1:
(1) preparation urea hydrogen peroxide mixture: add 708.2kg 30% hydrogen peroxide (3eq.) in the 2000L enamel still, 12.5kg Whitfield's ointment (0.1g/g) and 125kg urea (1.0eq.) are in 0～10 ℃ of insulation reaction.Reaction is finished, and is cooled to-10～0 ℃, and is centrifugal behind the insulated and stirred 3h, centrifugal solids 375L sherwood oil (3ml/g) drip washing, and filter cake is the urea hydrogen peroxide mixture, yield 80%, purity 98%;
(2) preparing product 2-chloropyridine-N-oxide compound
Reaction process: in the 2000L enamel still, add 360L ethyl acetate (3ml/g), 155kg Tetra hydro Phthalic anhydride (1.0eq.), 120kg dichloropyridine (1.0eq.).Reinforced finishing is warming up to 90～110 ℃ with system, adds 200kg urea hydrogen peroxide mixture (2.0eq), insulation reaction in system; After reacting completely, be cooled to 0～20 ℃, add the saturated sodium sulfite solution of 12kg to starch potassium iodide paper and no longer become blue, be 9～10 with 20% sodium hydroxide regulation system pH again, centrifugal, extraction, organic phase merges concentrated;
(3) make product: obtain product 93kg yield 68%.Liquid chromatography purity (HPLC): 96%.
Finished product test experience data are as follows:
H-NMR:(300MHZ, CDCl3), δ 7.37 (H on 4 carbon of pyridine ring), δ 7.57 (H on 5 carbon of pyridine ring) δ 7.60 (H on 3 carbon of pyridine ring) δ 8.30 (with on the pyridine ring-H on the adjacent carbon of N-O).
Embodiment 2:
(1) preparation urea hydrogen peroxide mixture: add 47.2kg 30% hydrogen peroxide (0.5eq.) in the 300L enamel still, 4.0kg ethylenediamine tetraacetic acid (EDTA) (0.08g/g) and 50kg urea (1.0eq.) are in 20～40 ℃ of insulation reaction.Reaction is finished, and is cooled to 5～15 ℃, and is centrifugal behind the insulated and stirred 1h, centrifugal solids 25L isopropyl acetate (0.5ml/g) drip washing, and filter cake is the urea hydrogen peroxide mixture, yield 78%, purity 98%;
(2) preparing product 2-methoxypyridine-N-oxide compound
Reaction process: in the 72L reaction flask, add 18L isopropyl acetate (15ml/g), 3.3kg diacetyl oxide (4eq.), 1.2kg 2-methoxypyridine (1.0eq), reinforced finishing, system is warming up to 30～40 ℃, in system, add 2.8kg urea hydrogen peroxide mixture (4.5eq), insulation reaction; After reacting completely, be cooled to 0～10 ℃, add 0.12kg saturated sodium bisulfite solution (no longer becoming blue), be 8～10 with 20% sodium bicarbonate regulation system pH again to starch potassium iodide paper, centrifugal, extraction, organic phase merges concentrated;
(3) make product: obtain product 813g, yield 62%; Liquid chromatography purity (HPLC): 95.6%.
Finished product test experience data are as follows:
H-NMR:(300MHZ, CDCl
3), δ 3.83 (OCH
3), δ 6.58 (H on 3 carbon of pyridine ring), δ 6.78 (H on 4 carbon of pyridine ring), δ 6.00 (H on 5 carbon of pyridine ring), δ 7.20 (H on 6 carbon of pyridine ring).
Embodiment 3:
(1) preparation urea hydrogen peroxide mixture: add 75.6kg 30% hydrogen peroxide (0.8eq.) in the 200L enamel still, 0.05kg potassium primary phosphate (0.001g/g) and 50kg urea (1.0eq.) are in 20～40 ℃ of insulation reaction.Reaction is finished, and is cooled to 0～5 ℃, and is centrifugal behind the insulated and stirred 0.5h, centrifugal solids 100L ethyl acetate (2ml/g) drip washing, and filter cake is the urea hydrogen peroxide mixture, yield 79%, purity 97%;
(2) preparing product 2-chloro-3-picoline oxynitride
Reaction process: in the 500L enamel still, add 252L ethyl acetate (9ml/g), 45.7kg diacetyl oxide (2.5eq.), 28kg 2-chloro-3-picoline (1.0eq.), reinforced finishing, system is warming up to 80～110 ℃, in system, add 16.8kg urea hydrogen peroxide mixture (1.0eq), insulation reaction; After reacting completely, be cooled to 30～50 ℃, add the saturated sodium sulfite solution of 2.8kg (no longer becoming blue), be 8～10 with saturated ammoniacal liquor regulation system pH again to starch potassium iodide paper, centrifugal, extraction, organic phase merges concentrated;
(3) make product: obtain product 19.7kg, yield 63.8%; Liquid chromatography purity (HPLC): 95.3%.
Finished product test experience data are as follows:
H-NMR:(300MHZ, CDCl
3), δ 2.34 (CH
3), δ 7.31 (H on 4 carbon of pyridine ring), δ 7.20 (H on 5 carbon of pyridine ring), δ 8.28 (H on 6 carbon of pyridine ring).
Embodiment 4:
(1) preparation urea hydrogen peroxide mixture: add 226.7kg 30% hydrogen peroxide (1.2eq.) in the 1000L enamel still, 0.8kg Seignette salt (0.008g/g) and 100kg urea (1.0eq.) are in 20～30 ℃ of insulation reaction.Reaction is finished, and is cooled to-5～5 ℃, and is centrifugal behind the insulated and stirred 1.5h, centrifugal solids 150L sherwood oil (1.5ml/g) drip washing, and filter cake is the urea hydrogen peroxide mixture, yield 77%, purity 98%;
(2) preparing product 2,5-dichloropyridine oxynitride
Reaction process: in the 200L enamel still, add 54L acetonitrile (3ml/g), 25.2kg Succinic anhydried (2.0eq.), 18.0kg 2,5-dichloropyridine (1.0eq.), reinforced finishing, system is warming up to 40～80 ℃, in system, adds 47.4kg urea hydrogen peroxide mixture (3.6eq), insulation reaction; After reacting completely, be cooled to 20～30 ℃, add 1.8kg saturated sodium thiosulfate solution (no longer becoming blue), be 9～10 with 20% sodium hydroxide regulation system pH again to starch potassium iodide paper, centrifugal, extraction, organic phase merges, and concentrates;
(3) make product: obtain product 13.2kg, yield 65.3%; Liquid chromatography purity (HPLC): 96.7%.
Finished product test experience data are as follows:
H-NMR:(300MHZ, CDCl
3), δ 7.79 (H on 3 carbon of pyridine ring), δ 7.61 (H on 4 carbon of pyridine ring), δ 8.50 (H on 6 carbon of pyridine ring).
As seen, adopt the method for the invention synthetic pyridines oxynitride, the raw material of employing is common reagent; easily obtain; environmental pollution is less, and low price, the chemical reaction condition gentleness; technology is reasonable; production safety is reliable, can directly obtain the higher degree finished product after the reaction, and ripe on this Technology; the ability that possesses large-scale production is a synthesis technique feasible, that pollution is lower.
Claims (9)
1. synthetic method for preparing pyridine nitric oxide is characterized in that concrete preparation process is as follows:
(1) preparation urea hydrogen peroxide mixture: hydrogen peroxide and stablizer and urea are in 0～40 ℃ of insulation reaction; Reaction is finished, and is cooled to-10～15 ℃, and is centrifugal behind insulated and stirred 0.5～3h, and filter cake obtains the urea hydrogen peroxide mixture with ester class or ether solvent drip washing;
Wherein the mol ratio of urea and hydrogen peroxide is 1: 0.5～3, and stabilizing agent dosage is every gram urea 0.001～0.1 gram, and ester class or ethers consumption are every gram urea 0.5～3.5ml;
(2) preparation
Reaction process: in the presence of ester class or nitrile solvents and acid anhydrides, add main raw material
System is warming up to 30～110 ℃, and 30～110 ℃ of temperature controls add urea hydrogen peroxide mixture insulation reaction; After reacting completely, be cooled to 0～50 ℃, add saturated reductibility reagent solution to starch potassium iodide paper and no longer become blue, adding alkaline solution regulation system pH value is 8～10 to making pH value, centrifugal, extraction, concentrated;
R wherein
1～R
5Be alkyl, the protium of replacement or polysubstituted C1～C3, hydroxyl, methoxyl group, oxyethyl group, halogen (F, Cl, Br, I); Ester class or nitrile solvents consumption are every gram main raw material
3～15mL; Main raw material
With the mol ratio of acid anhydrides be 1: 1～4; Main raw material
With urea hydrogen peroxide mixture mol ratio be 1: 1～4.5;
(3) make product: promptly obtain product
2. according to the said a kind of synthetic method for preparing pyridine nitric oxide of claim 1, it is characterized in that in the said step (1), the mol ratio of urea and hydrogen peroxide is 1: 0.5～2; Stabilizing agent dosage is every gram urea 0.001～0.05 gram, and ester class or ethers consumption are every gram urea 0.5～2.5ml.
3. according to the said a kind of synthetic method for preparing pyridine nitric oxide of claim 1, it is characterized in that ester class or the nitrile solvents consumption in the said step (2) is every gram main raw material
3～10mL; Main raw material
With the mol ratio of acid anhydrides be 1: 1～3; Main raw material
With urea hydrogen peroxide mixture mol ratio be 1: 1～3.5; The alkaline solution consumption is 9～10 for making the system pH value.
4. according to the said a kind of synthetic method for preparing pyridine nitric oxide of claim 2, it is characterized in that in the said step (1), the mol ratio of urea and hydrogen peroxide is 1: 0.5～1.5; Stabilizing agent dosage is every gram urea 0.001～0.01 gram, and ester class or ethers consumption are every gram urea 0.5～2ml.
5. according to the said a kind of synthetic method for preparing pyridine nitric oxide of claim 3, it is characterized in that ester class or the nitrile solvents consumption in the said step (2) is every gram main raw material
4～8mL; Main raw material
With the mol ratio of acid anhydrides be 1: 1～2.5; Main raw material
With urea hydrogen peroxide mixture mol ratio be 1: 1～2.5; The alkaline solution consumption is 9～10 for making the system pH value.
6. according to the said a kind of synthetic method for preparing pyridine nitric oxide of claim 1, it is characterized in that the stablizer in the said step (1) is potassium primary phosphate, Seignette salt, citric acid, Whitfield's ointment and ethylenediamine tetraacetic acid (EDTA); Ester class or ether solvent are sherwood oil, ethyl acetate, isopropyl acetate.
7. according to the said a kind of synthetic method for preparing pyridine nitric oxide of claim 1, it is characterized in that ester class or the nitrile solvents in the said step (2) is ethyl acetate, isopropyl acetate, acetonitrile; Acid anhydrides is diacetyl oxide, Tetra hydro Phthalic anhydride, maleic anhydride, Succinic anhydried; Reductibility reagent is sodium bisulfite, S-WAT, Sulfothiorine, sodium sulphite, ferrous sulfate; Alkaline solution is sodium hydroxide, potassium hydroxide, sodium bicarbonate, yellow soda ash, ammoniacal liquor.
8. according to the said a kind of synthetic method for preparing pyridine nitric oxide of claim 6, it is characterized in that the stablizer in the said step (1) is preferably citric acid, Whitfield's ointment and ethylenediamine tetraacetic acid (EDTA); Ester class or ether solvent are sherwood oil, isopropyl acetate.
9. according to the said a kind of synthetic method for preparing pyridine nitric oxide of claim 7, it is characterized in that ester class or the nitrile solvents in the said step (2) is ethyl acetate, isopropyl acetate, acetonitrile etc.; Acid anhydrides comprises diacetyl oxide, Tetra hydro Phthalic anhydride, Succinic anhydried etc.; Reductibility reagent is preferably sodium bisulfite, S-WAT, Sulfothiorine etc.; Alkaline solution is preferably sodium hydroxide, sodium bicarbonate, ammoniacal liquor etc.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104628636A (en) * | 2015-02-02 | 2015-05-20 | 南阳师范学院 | Synthesis method of pyridine heterocycle oxynitrides |
| CN105646292A (en) * | 2016-03-01 | 2016-06-08 | 重庆康乐制药有限公司 | Preparation method of dapoxetine N-oxide |
| CN110563613A (en) * | 2019-09-09 | 2019-12-13 | 上海理工大学 | synthesis method and application of urea peroxide |
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| CN1418871A (en) * | 2002-11-28 | 2003-05-21 | 陶华西 | Process for preparing peroxide urea |
| CN101698659A (en) * | 2009-11-12 | 2010-04-28 | 董婧 | Synthesis method of 2-pyridine formaldoxime |
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2011
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Patent Citations (2)
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| CN1418871A (en) * | 2002-11-28 | 2003-05-21 | 陶华西 | Process for preparing peroxide urea |
| CN101698659A (en) * | 2009-11-12 | 2010-04-28 | 董婧 | Synthesis method of 2-pyridine formaldoxime |
Non-Patent Citations (2)
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| 《Tetrahedron Letters》 20001231 Stéphane Caron, et al. A practical, efficient, and rapid method for the oxidation of electron deficient pyridines using trifluoroacetic anhydride and hydrogen peroxide-urea complex 2299-2302 1-9 第41卷, * |
| STÉPHANE CARON, ET AL.: "A practical, efficient, and rapid method for the oxidation of electron deficient pyridines using trifluoroacetic anhydride and hydrogen peroxide–urea complex", 《TETRAHEDRON LETTERS》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104628636A (en) * | 2015-02-02 | 2015-05-20 | 南阳师范学院 | Synthesis method of pyridine heterocycle oxynitrides |
| CN104628636B (en) * | 2015-02-02 | 2017-03-15 | 南阳师范学院 | The synthetic method of pyridines heterocycle oxynitride |
| CN105646292A (en) * | 2016-03-01 | 2016-06-08 | 重庆康乐制药有限公司 | Preparation method of dapoxetine N-oxide |
| CN110563613A (en) * | 2019-09-09 | 2019-12-13 | 上海理工大学 | synthesis method and application of urea peroxide |
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Application publication date: 20111123 |