CN104803928A - Synthetic method of high-purity veterinary drug quinocetone - Google Patents
Synthetic method of high-purity veterinary drug quinocetone Download PDFInfo
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- CN104803928A CN104803928A CN201510170186.XA CN201510170186A CN104803928A CN 104803928 A CN104803928 A CN 104803928A CN 201510170186 A CN201510170186 A CN 201510170186A CN 104803928 A CN104803928 A CN 104803928A
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- quinocetone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/50—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to ring nitrogen atoms
- C07D241/52—Oxygen atoms
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Abstract
The invention discloses a synthetic method of high-purity veterinary drug quinocetone. The synthetic method comprises steps as follows: petroleum ether, mequindox, benzaldehyde and pyridine are sequentially added to a reaction container equipped with a stirrer, a water separator and a condenser pipe, stirred and heated to 60 DEG C-90 DEG C, have a reflux reaction for 6-8 hours and then are cooled to the temperature below 30 DEG C, subjected to suction filtration and dried, and quinocetone with purity higher than 98% and yield higher than 87% is obtained; the feeding molar ratios of mequindox to benzaldehyde to pyridine is 1: (1.05-1.1) : 0.1, and the feeding mass of petroleum ether is 3-5 times of that of mequindox. Water in the reaction is constantly removed by the water separator, so that the reaction is smoothly performed in the positive direction, and higher yield is obtained in shorter time; meanwhile, products are not required to be refined in the preparation process, and after the reaction ends, not completely reacted raw materials and a catalyst pyridine are still dissolved in petroleum ether and can be removed through suction filtration and drying. The technological process is greatly simplified, the liquid waste pollution is reduced, and the production cost is reduced.
Description
Technical field
The present invention relates to a kind of synthetic method of veterinary drug, particularly relate to a kind of synthetic method of high purity veterinary drug Quinocetone.
Background technology
Quinocetone, chemical name: 3-methyl-2-cinnamicacyl-quinoxaline-1,4-dioxide is a kind of veterinary drug developed by Lanzhou Livestock and Animal Drug Inst., Chinese Academy of Agricultural Science, can be used as fodder additives.Quinocetone is by the synthesis of anti-bacteria DNA; suppress pathogenic agent microbial growth breeding in digestive tube; protection intestinal beneficial flora and intestines wall are not encroached on by microorganism or parasite, thus reach the object reducing disease and occur, promote growth of animal, improve efficiency of feed utilization.Quinocetone toxicity is extremely low simultaneously, and excretion is fast, does not accumulate, noresidue, without three-induced effect, and use safety.Both be applicable to pig, be also applicable to fowl and aquatic products, be also applicable to the prophyiaxis and promoting growth of cub, poult.
Current Quinocetone mainly reacts obtained by Claisen-Schmit, shown in (1) by mequindox and phenyl aldehyde under the effect of catalyzer:
Chinese patent 200410073376.1 adopts alcohols or dimethyl formamide to make solvent, mequindox and phenyl aldehyde are raw material, under the effect of basic catalyst, react after 5 hours through filtering at 20 ~ 80 DEG C, 95% washing with alcohol, dry obtained target product Quinocetone.The large usage quantity of the method Raw phenyl aldehyde and catalyzer, and reaction needs to use a large amount of washing with alcohol after terminating, and adds operation steps and production cost, and there is waste water handling problem, increased the weight of environmental protection pressure.
Chinese patent 201110327882.9 adopts methyl alcohol to be solvent, and thanomin makes catalyzer, and mequindox and phenyl aldehyde are raw material, reacts through cooling after 8 ~ 48 hours, suction filtration, a large amount of methanol wash at 38 ~ 45 DEG C, obtained target product Quinocetone after dry.It is longer to there is the reaction times in this reaction, and organic solvent methanol usage is large, and product needs the problems such as refining.
Summary of the invention
In order to solve Problems existing in existing Quinocetone technology of preparing, the invention provides a kind of low cost, synthesis method of quinocetone rapidly and efficiently, products therefrom has higher purity and yield, without the need to the separating-purifying of complexity in simultaneous reactions process, simplify technical process, be more suitable for suitability for industrialized production.
The present invention is achieved through the following technical solutions:
(1) in reaction vessel, add sherwood oil, mequindox, phenyl aldehyde and pyridine successively, be heated with stirring to 60 ~ 90 DEG C, back flow reaction 6 ~ 8 hours, described reactor is provided with water trap, and water trap is provided with prolong;
(2) reaction terminates rear cooling, suction filtration, namely obtains Quinocetone after oven dry.
Further, the sherwood oil boiling range described in step (1) is 60 ~ 90 DEG C or 90 ~ 120 DEG C.
Further, the cooling temperature described in step (2) is less than 30 DEG C.
Benzene feedstock formaldehyde and catalyst pyridine have good solubility in sherwood oil, and mequindox 30 DEG C is solvable
In sherwood oil, step (1) selects sherwood oil to make solvent, slightly does heating material can be made to be uniformly dispersed in system by stirring, and sherwood oil can reach good azeotropic effect with reacting the water that generate in addition.Sherwood oil is oils, is the paraffins mixture of low relative molecular mass, and industrial conventional sherwood oil has the boiling range specifications such as 30 ~ 60 DEG C, 60 ~ 90 DEG C, 90 ~ 120 DEG C.When the sherwood oil that boiling range is too low and water azeotropic, temperature is lower, causes speed of response excessively slow, and therefore step (1) selects boiling range to be that the sherwood oil of 60 ~ 90 DEG C or 90 ~ 120 DEG C makes solvent.
Further, the sherwood oil boiling range described in step (1) is 60 ~ 90 DEG C.
Mequindox and toluene generation condensation reaction in the present invention, the by product of generation is water.The method that constant boiling mixture distills is utilized in experimentation, being distilled by sherwood oil-water azeotrope enters in water trap, wherein upper organic phase toluene continues to flow and gets back in reaction vessel, water is then by managing separated removal under water trap, reaction is carried out to positive dirction smoothly, ensures the high yield obtaining more than 87% within a short period of time.When the water yield in water trap no longer increases, react completely.
Due to product Quinocetone slightly soluble in sherwood oil, reaction terminate after system is cooled to less than 30 DEG C, product can be separated out, and unreacted phenyl aldehyde and catalyst pyridine are still dissolved in sherwood oil completely, by suction filtration, dry the Quinocetone that can obtain purity more than 98%.Highly purified product can be obtained without the need to the separating-purifying of complexity and purification step in preparation process, decrease technical process and solvent usage quantity, reduce industrial cost, alleviate environmental protection pressure.
Further, the molar ratio of the mequindox described in step (1), phenyl aldehyde, pyridine is 1:1.05 ~ 1.1:0.1, and the mass ratio that feeds intake of sherwood oil and mequindox is 1:3 ~ 5.The present invention, owing to have selected suitable solvent, by means of the effect of water trap simultaneously, adopts a small amount of catalyzer can reach good reaction effect.
As further preferred version:
Step (1) Raw mequindox, phenyl aldehyde, pyridine molar ratio are 1:1.1:0.1, and the mass ratio that feeds intake of sherwood oil and mequindox is 1:4; Heating temperature is 80 DEG C, 7 hours reaction times.
Beneficial effect of the present invention is:
1, the present invention adopts water trap constantly to remove water byproduct in reaction process, ensure that reaction is carried out to positive dirction smoothly, can at the higher yield of short period acquisition.
2, the present invention selects sherwood oil to make solvent, product Quinocetone slightly soluble in sherwood oil, and phenyl aldehyde, pyridine and mequindox solvability in sherwood oil is better, therefore after reaction terminates cooling, product Quinocetone is separated out, and unreacted raw material and catalyst pyridine are still dissolved in toluene completely, by means of only suction filtration, dry the retained material and catalyzer that can remove in Quinocetone, the product purity of more than 98% can be reached by simple operation method.Enormously simplify technical process, reduce production cost, decrease discharging of waste liquid amount, there is the advantage of energy-conserving and environment-protective.
Embodiment
Below in conjunction with specific experiment embodiment, the present invention is described in further detail, but the present invention does not limit by embodiment.
Embodiment 1
(1) stirring rake is being housed, prolong, in the there-necked flask of water trap, add the sherwood oil 327g that boiling range is 60 ~ 90 DEG C successively, mequindox 109g (0.5mol), phenyl aldehyde 58.3g (0.55mol), pyridine 3.95g (0.05mol), open and stir, after heating, material dissolves rapidly, continue to be warming up to 80 DEG C of backflows, in reflux course, the water that reaction produces and solvent sherwood oil are distilled out together by azeotropic and enter in water trap, its at the middle and upper levels sherwood oil continue to flow and get back in there-necked flask, lower aqueous layer is then removed by being in control under water trap to be separated, temperature rising reflux, in reflux course, the water that reaction produces is separated by water trap, react 7 hours,
(2) by step (1) gained reaction solution cooling down to 30 DEG C, have faint yellow solid to separate out, through suction filtration, 90 DEG C of oven dry obtain Quinocetone 141.5g, and purity is 99.1%, and yield is 92.4%.
Embodiment 2 ~ 3
Mequindox, the pyridine of the employing operation steps identical with embodiment 1 and same amount prepare Quinocetone, the sherwood oil of different amounts and phenyl aldehyde, and different temperature of reaction and reaction times, obtained experimental data is as shown in table 1:
Table 1:
Comparative example 1
(1) stirring rake is being housed, in the there-necked flask of prolong, add sherwood oil 327g, mequindox 109g (0.5mol), phenyl aldehyde 58.3g (0.55mol), pyridine 3.95g (0.05mol) that boiling range is 60 ~ 90 DEG C successively, open and stir, after heating, material dissolves rapidly, continues to be warming up to 65 DEG C of backflows, because the water generated in reaction process can not be effectively separated, reaction reaches 65 DEG C and namely reaches reflux temperature, reacts 7 hours;
(2) by step (1) gained reaction solution cooling down to 30 DEG C, have faint yellow solid to separate out, through suction filtration, 90 DEG C of oven dry obtain Quinocetone 140.6g, and purity is 85.6%, and yield is 78.6%.
Comparative example 2
(1) stirring rake is being housed, prolong, in the there-necked flask of water trap, add phenyl aldehyde 58.3g (0.55mol), mequindox 109g (0.5mol), pyridine 3.95g (0.05mol) successively, be heated with stirring to 80 DEG C, material is thickness comparatively, continues stirring reaction 7 hours;
(2) by step (1) gained reactant cooling down to 30 DEG C, product is not had to separate out, and material still very thickness, cannot suction filtration, react unsuccessfully.
Comparative example 3
(1) stirring rake is being housed, prolong, in the there-necked flask of water trap, add methyl alcohol 128g (4mol), mequindox 109g (0.5mol), phenyl aldehyde 58.3g (0.55mol), pyridine 3.95g (0.05mol) successively, open and stir, after heating, material dissolution is slower, continue to be warming up to 60 DEG C of backflows, in water trap, liquid is without layering, the moisture of generation cannot be left away and remove, and reacts 7 hours;
(2) by step (1) gained reaction solution cooling down to 30 DEG C, have faint yellow solid to separate out, through suction filtration, 100 DEG C of oven dry obtain Quinocetone 78.5g, and purity is 79.8%, and yield is 40.9%.
By comparative example 1 ~ 3 and comparative example 1 ~ 3, can reach a conclusion: in the present invention, the use of water trap is the key accelerating speed of reaction, water trap can remove the water byproduct that reaction generates effectively fast, reaction is carried out to positive dirction smoothly, and water is conducive to after removing raising temperature of reaction thus further accelerating speed of reaction simultaneously.The selection also outbalance of solvent, its solvability to raw material need be considered during selective solvent, good azeotropic effect can be reached with water byproduct simultaneously, solvent sherwood oil selected by the present invention, can comparatively good dissolving raw material and catalyzer, and to product Quinocetone slightly soluble, therefore reaction terminate after by means of only simple cooling, drying operation can by product separation, obtain highly purified Quinocetone, enormously simplify production technique, be more of value to suitability for industrialized production.
Claims (7)
1. a synthetic method for high purity veterinary drug Quinocetone, is characterized in that, described synthetic method comprises the following steps:
(1) in reaction vessel, add sherwood oil, mequindox, phenyl aldehyde and pyridine successively, be heated with stirring to 60 ~ 90 DEG C, back flow reaction 6 ~ 8 hours;
(2) reaction terminates rear cooling, suction filtration, namely obtains Quinocetone after oven dry;
Reactor wherein described in step (1) is provided with water trap, and water trap is provided with prolong.
2. the synthetic method of high purity veterinary drug Quinocetone as claimed in claim 1, it is characterized in that, the sherwood oil boiling range described in step (1) is 60 ~ 90 DEG C or 90 ~ 120 DEG C.
3. the synthetic method of high purity veterinary drug Quinocetone as claimed in claim 1, it is characterized in that, the molar ratio of the mequindox described in step (1), phenyl aldehyde, pyridine is 1:1.05 ~ 1.1:0.1, and the mass ratio that feeds intake of sherwood oil and mequindox is 1:3 ~ 5.
4. the synthetic method of high purity veterinary drug Quinocetone as claimed in claim 1, it is characterized in that, the cooling temperature described in step (2) is less than 30 DEG C.
5. the synthetic method of high purity veterinary drug Quinocetone as claimed in claim 3, it is characterized in that, mequindox described in step (1), phenyl aldehyde, pyridine molar ratio are 1:1.1:0.1, and the mass ratio that feeds intake of sherwood oil and mequindox is 1:4.
6. the synthetic method of high purity veterinary drug Quinocetone as claimed in claim 1, it is characterized in that, the Heating temperature described in step (1) is 80 DEG C, 7 hours reaction times.
7. the synthetic method of high purity veterinary drug Quinocetone as claimed in claim 2, it is characterized in that, the sherwood oil boiling range described in step (1) is 60 ~ 90 DEG C.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566234A (en) * | 2015-12-24 | 2016-05-11 | 南阳市天华制药有限公司 | Quinocetone preparation method |
| CN110003124A (en) * | 2019-03-22 | 2019-07-12 | 苏州华道生物药业股份有限公司 | A kind of synthetic method of quinocetone |
Citations (5)
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| CN1197068A (en) * | 1997-04-21 | 1998-10-28 | 中国农业科学院中兽医研究所 | Compound and synthetic process of 3-methyl-2-phenylethylene keto-quinooxaline-1.4-dioxide |
| CN1785979A (en) * | 2004-12-07 | 2006-06-14 | 中国农业科学院兰州畜牧与兽药研究所 | Preparation method of 3-methyl-2-cinoamoyl-quinoxaline-1,4-dioxide |
| CN101402612A (en) * | 2008-11-14 | 2009-04-08 | 刘占领 | Synthesis of quinocetone |
| CN102311397A (en) * | 2011-10-25 | 2012-01-11 | 湖南科技大学 | High-efficient quinocetone synthetic method |
| CN102329272A (en) * | 2011-11-01 | 2012-01-25 | 荆州市新元生物科技有限公司 | Method for preparing quinocetone |
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2015
- 2015-04-13 CN CN201510170186.XA patent/CN104803928A/en active Pending
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| CN1197068A (en) * | 1997-04-21 | 1998-10-28 | 中国农业科学院中兽医研究所 | Compound and synthetic process of 3-methyl-2-phenylethylene keto-quinooxaline-1.4-dioxide |
| CN1785979A (en) * | 2004-12-07 | 2006-06-14 | 中国农业科学院兰州畜牧与兽药研究所 | Preparation method of 3-methyl-2-cinoamoyl-quinoxaline-1,4-dioxide |
| CN101402612A (en) * | 2008-11-14 | 2009-04-08 | 刘占领 | Synthesis of quinocetone |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566234A (en) * | 2015-12-24 | 2016-05-11 | 南阳市天华制药有限公司 | Quinocetone preparation method |
| CN110003124A (en) * | 2019-03-22 | 2019-07-12 | 苏州华道生物药业股份有限公司 | A kind of synthetic method of quinocetone |
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Application publication date: 20150729 |