CN101967101A - Method for preparing 5-nitrosalicylaldehyde - Google Patents
Method for preparing 5-nitrosalicylaldehyde Download PDFInfo
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- CN101967101A CN101967101A CN2010105052343A CN201010505234A CN101967101A CN 101967101 A CN101967101 A CN 101967101A CN 2010105052343 A CN2010105052343 A CN 2010105052343A CN 201010505234 A CN201010505234 A CN 201010505234A CN 101967101 A CN101967101 A CN 101967101A
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Abstract
The invention belongs to the technical field of important raw material for preparing dronedarone, and particularly relates to a method for preparing improved 5-nitrosalicylaldehyde. The 5-nitrosalicylaldehyde is prepared from p-nitrophenol serving as a raw material by improving Duff reaction and hexamethylenetetramine reaction, wherein an acid solvent is added during the reaction, the stickiness of polyphosphoric acid is reduced, and the tracing and detection of the reaction are facilitated. The invention has the advantages of simple and reliable method, short steps, high reaction yield, low production cost and relatively high implementation value and social and economical benefits.
Description
Technical field
The invention belongs to the technical field of the required important source material of preparation Dronedarone, be specially a kind of preparation method of the 5-of improvement nitrosalicylaldehyde.
Background technology
The 5-nitrosalicylaldehyde is a kind of fine-chemical intermediate that medicine, agricultural chemicals, dyestuff and spices are produced that is widely used in.
Along with the quickening of social process, the pressure that people bear is increasing, and the quantity of cardiovascular patient also constantly increases, and therefore, the research of cardiovascular agent more and more obtains people's attention.Dronedarone (dronedarone hydrochloride); chemistry 2-normal-butyl-3-[4-by name (the amino propoxy-of 3-di-n-butyl) benzoyl]-5-methylsulfonyl amido cumarone; be a kind of polarization inhibitor by Frenchman's research and development, the clinical treatment heart disorder that is mainly used in.
The 5-nitrosalicylaldehyde is one of important source material of synthetic Dronedarone, and in luminescent material and coordination chemistry, the 5-nitrosalicylaldehyde also is an important synthesis intermediates.In recent years, the property research of 5-nitrosalicylaldehyde series title complex finds that this series title complex has certain anticancer and bacteriostatic activity, can be used as the potential chemicals.Therefore, the new synthetic method and the technology of research and development 5-nitrosalicylaldehyde have good economic benefits and social benefit.
At present, the synthetic method of synthetic 5-nitrosalicylaldehyde roughly is divided into two classes both at home and abroad: salicylic aldehyde nitrofication process (nitration reaction) and p-NP formylation method (improvement Duff reaction).The flow process of Whitfield's ointment nitrofication process such as figure below:
The shortcoming of salicylic aldehyde nitrofication process is: the nitration reaction poor controllability, and the reactivity hazard height, and the separation and purification of nitration product is complicated unusually.
People such as Yuji Suzuki and Zhang Hua adopt the improvement Duff reaction in the pertinent literature, are raw material with p-NP and vulkacit H, adopt 75% polyphosphoric acid or methylsulfonic acid or trifluoroacetic acid to make catalyzer, synthetic 5-nitrosalicylaldehyde.Its technical process such as figure below:
The problem that this method exists is: when methylsulfonic acid or trifluoroacetic acid were catalyzer, the productive rate of product was low, had only 57% and 35% respectively.
Processing step when adopting 75% polyphosphoric acid to make catalyzer is: polyphosphoric acid and p-NP are joined in the there-necked flask that electronic stirring and thermometer are housed, constantly be heated with stirring to 100 ℃ in oil bath, add vulkacit H in batches, controlled temperature finishes at 100 ℃, and reaction is 2 hours under this temperature, reaction finishes, and removes oil bath, adds frozen water in reaction flask, constantly stir cool to room temperature down, separate out light yellow crystal, filter drying, get the 5-nitrosalicylaldehyde, yield 51%.But the viscosity of polyphosphoric acid is unfavorable for following the tracks of and detection reaction, is difficult for realizing industrialization, and reacts very exothermic in the adding vulkacit H process, easy material spray, and there is certain danger in reaction.
Summary of the invention
Purpose of the present invention is exactly the preparation method that a kind of 5-nitrosalicylaldehyde is provided at the problem of above-mentioned existence, and this method technology is easy, and the yield height is safe, is fit to industrial production.
The preparation method of 5-nitrosalicylaldehyde of the present invention (formula I compound) is to be raw material with the p-NP, makes through improving the reaction of Duff reaction and vulkacit H,
Ⅰ
Its step is as follows:
Under the stirring at room condition, earlier the catalyzer polyphosphoric acid is dissolved in the acid solvent, then to the mixture that wherein adds vulkacit H and p-NP in batches, after adding, be warming up to backflow, reacted 3-8 hour, at last reaction solution is transferred in the water, obtain light yellow solid, suction filtration gets the 5-nitrosalicylaldehyde.
Wherein, described acid solvent is a kind of in anhydrous formic acid, the anhydrous acetic acid or both mixtures, the monitoring that helps reacting.
Described catalyzer is concentration 75% polyphosphoric acid.
The temperature of reaction of described improvement daf is 100-140 ℃.
In reaction scheme of the present invention, reaction (CH
2)
6N
4The expression vulkacit H, PPA represents polyphosphoric acid.
The product that obtains is carried out infrared spectra and nuclear-magnetism detection, and its characterization parameter is as follows:
Infrared spectra (KBr, cm
-1): 3153 cm
-1, 2743 cm
-1, 1692 cm
-1, 1571 cm
-1, 1510 cm
-1, 1490 cm
-1, 1461 cm
-1, 1402 cm
-1, 1346 cm
-1, 1346 cm
-1, 1341cm
-1, 921 cm
-1, 846 cm
-1, 716 cm
-1
1H?NMR?(300?MHz,?CDCl3)?δ:?11.61?(s,?1H,OH),?10.01?(?S,1H,CHO),?8.56?(S,1H,?ArH),?8.42?(m,?1H,ArH),?7.14?(m,?1H,ArH)。
Beneficial effect of the present invention is: add acid solvent in reaction process, reduced the viscosity of polyphosphoric acid, tracking that helps reacting and detection; And adjusted order of addition(of ingredients), avoided the danger of material spray; Improve temperature of reaction, prolong the reaction times, improve yield, can realize suitability for industrialized production.
In a word, operational path of the present invention is easy, and the yield height reaches 68.8%, and the HPLC purity detecting is 91.8%, and is safe, is fit to industrial production, has bigger implementary value and economic results in society.
Embodiment
The invention will be further described with specific embodiment below, but be not to be intended to limit protection scope of the present invention.
Embodiment 1:
Under the stirring at room condition, with 2780g concentration is that 75% polyphosphoric acid is dissolved in the 600mL anhydrous formic acid, add the mixture of vulkacit H 280g and p-NP 287g in batches, finish, be warming up to 110 ℃, reacted 5 hours, reaction solution is transferred in the 5L water, obtained lurid solid, suction filtration gets crude product 220g, yield 68.8%, HPLC purity detecting: 91.8%.
Infrared spectra (KBr, cm
-1): 3153 cm
-1, 2743 cm
-1, 1692 cm
-1, 1571 cm
-1, 1510 cm
-1, 1490 cm
-1, 1461 cm
-1, 1402 cm
-1, 1346 cm
-1, 1346 cm
-1, 1341cm
-1, 921 cm
-1, 846 cm
-1, 716 cm
-1
1H?NMR?(300?MHz,?CDCl3)?δ:?11.61?(s,?1H,OH),?10.01?(?S,1H,CHO),?8.56?(S,1H,?ArH),?8.42?(m,?1H,ArH),?7.14?(m,?1H,ArH)。
Embodiment 2:
Under the stirring at room condition, with 2780g concentration is that 80% polyphosphoric acid is dissolved in the 600mL anhydrous acetic acid, add the mixture of vulkacit H 280g and p-NP 287g in batches, finish, be warming up to 120 ℃, reacted 3 hours, reaction solution is transferred in the 5L water, obtained lurid solid, suction filtration gets crude product 210g, yield 65.6%, HPLC purity detecting: 91.1%.
Infrared spectra (KBr, cm
-1): 3152cm
-1, 2741 cm
-1, 1693 cm
-1, 1571 cm
-1, 1511 cm
-1, 1492 cm
-1, 1462 cm
-1, 1402 cm
-1, 1346 cm
-1, 1341cm
-1, 921 cm
-1, 847 cm
-1, 715 cm
-1
1H?NMR?(300?MHz,?CDCl3)?δ:?11.62?(s,?1H,OH),?10.00?(?S,1H,CHO),?8.59(S,1H,?ArH),?8.44?(m,?1H,ArH),?7.16?(m,?1H,ArH)。
Embodiment 3:
Under the stirring at room condition, with 2780g concentration is that 80% polyphosphoric acid is dissolved in the 600mL anhydrous formic acid, add the mixture of vulkacit H 280g and p-NP 287g in batches, finish, be warming up to 130 ℃, reacted 8 hours, reaction solution is transferred in the 5L water, obtained tan solid, suction filtration gets crude product 215g, yield 67.2%, HPLC purity detecting: 90.3%.
Infrared spectra (KBr, cm
-1): 3151 cm
-1, 2742 cm
-1, 1691 cm
-1, 1570 cm
-1, 1513 cm
-1, 1491 cm
-1, 1463 cm
-1, 1401 cm
-1, 1347 cm
-1, 1346 cm
-1, 1341cm
-1, 921 cm
-1, 843 cm
-1, 715 cm
-1
1H?NMR?(300?MHz,?CDCl3)?δ:?11.64?(s,?1H,OH),?10.02?(?S,1H,CHO),?8.56?(S,1H,?ArH),?8.43(m,?1H,ArH),?7.15?(m,?1H,ArH)。
Embodiment 4:
Under the stirring at room condition, with 2780g concentration is that 80% polyphosphoric acid is dissolved in the 600mL anhydrous acetic acid, add the mixture of vulkacit H 280g and p-NP 287g in batches, finish, be warming up to 120 ℃, reacted 6 hours, reaction solution is transferred in the 5L water, obtained tan solid, suction filtration gets crude product 208g, yield 65.1%, HPLC purity detecting: 89.4%.
Infrared spectra (KBr, cm
-1): 3150 cm
-1, 2746 cm
-1, 1691 cm
-1, 1573 cm
-1, 1512 cm
-1, 1491 cm
-1, 1463 cm
-1, 1401 cm
-1, 1347 cm
-1, 1341cm
-1, 921 cm
-1, 845 cm
-1, 718 cm
-1
1H?NMR?(300?MHz,?CDCl3)?δ:?11.66?(s,?1H,OH),?10.04?(?S,1H,CHO),?8.58?(S,1H,?ArH),?8.41?(m,?1H,ArH),?7.13?(m,?1H,ArH)。
Claims (4)
1. the preparation method of a 5-nitrosalicylaldehyde is to be raw material with the p-NP, makes through improving the reaction of Duff reaction and vulkacit H, and its step is as follows:
Under the stirring at room condition, earlier the catalyzer polyphosphoric acid is dissolved in the acid solvent, then to the mixture that wherein adds vulkacit H and p-NP in batches, after adding, be warming up to backflow, reacted 3-8 hour, at last reaction solution is transferred in the water, obtain light yellow solid, suction filtration gets the 5-nitrosalicylaldehyde.
2. preparation method according to claim 1 is characterized in that, described acid solvent is a kind of in anhydrous formic acid, the anhydrous acetic acid or both mixtures.
3. preparation method according to claim 1 is characterized in that, the catalyzer of described improvement Duff reaction is 75% polyphosphoric acid.
4. preparation method according to claim 1 is characterized in that, the temperature of described improvement Duff reaction is 100-140 ℃.
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| CN2010105052343A CN101967101A (en) | 2010-10-13 | 2010-10-13 | Method for preparing 5-nitrosalicylaldehyde |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111689864A (en) * | 2020-06-28 | 2020-09-22 | 常州工程职业技术学院 | Method for synthesizing 5-nitro salicylaldehyde |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH1045733A (en) * | 1996-08-01 | 1998-02-17 | Teijin Ltd | Production of 2-(4-alkoxy-3-cyanophenyl)thiazole derivative |
| CN1506347A (en) * | 2002-12-09 | 2004-06-23 | ˹���ػ�ѧ��Ʒ�ɷ�����˾ | Fluoridized benzaldehyde |
-
2010
- 2010-10-13 CN CN2010105052343A patent/CN101967101A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH1045733A (en) * | 1996-08-01 | 1998-02-17 | Teijin Ltd | Production of 2-(4-alkoxy-3-cyanophenyl)thiazole derivative |
| CN1506347A (en) * | 2002-12-09 | 2004-06-23 | ˹���ػ�ѧ��Ʒ�ɷ�����˾ | Fluoridized benzaldehyde |
Non-Patent Citations (4)
| Title |
|---|
| 卜鑫宇: "5-硝基水杨醛合成方法的研究", 《中国优秀硕士学位论文数据库 工程科技Ⅰ辑》 * |
| 张维庆: "改进Duff反应合成5-硝基水杨醛", 《化学时刊》 * |
| 郑凡: "非布索坦的合成", 《中国医药工业杂志》 * |
| 黄晓龙: "利用改进的Duff反应合成对二甲氨基苯甲醛", 《化学试剂》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111689864A (en) * | 2020-06-28 | 2020-09-22 | 常州工程职业技术学院 | Method for synthesizing 5-nitro salicylaldehyde |
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Application publication date: 20110209 |