CN101275153A - Enzyme-chemical method for synthesizing ethoxyquinoline - Google Patents
Enzyme-chemical method for synthesizing ethoxyquinoline Download PDFInfo
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- CN101275153A CN101275153A CNA2007100385199A CN200710038519A CN101275153A CN 101275153 A CN101275153 A CN 101275153A CN A2007100385199 A CNA2007100385199 A CN A2007100385199A CN 200710038519 A CN200710038519 A CN 200710038519A CN 101275153 A CN101275153 A CN 101275153A
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Abstract
The present invention provides a zymochemistry method of preparing ethopabate which is environment friendly, processed by method of biocatalysis, relatively lower price, high yield, belonging to biocatalysis organic synthesis technical field. The synthesis of ethopabate is divided into two steps. Firstly, 3-hydroxy-4-methyl-2-pentanone is transformed by isobutyraldehyde or 4-methyl-2, 3-pentanedione using biocatalysis technology, a key precursor 4-methylpenteneis-3-ketone-2 is produced by dehydration; then ethopabate is produced by the condensation of 4-methylpenteneis-3-ketone-2 and 4-aminophenylethyl ether, the reaction trends to complete, greatly enhancing yield and purification of product. According to the operation of the invention, compared with the established synthesis method, the invention avoids use of concentrated acid, greatly reducing reaction temperature, greatly shortening reaction time, greatly improving conversion and utility of raw material, completely eradicating the pollution threat of ethopabate to the environment, realizing production in a friendly environment.
Description
Technical field
This patent relates to a kind of eco-friendly, carries out in the mode of biocatalysis, and is relatively inexpensive, and the zymochemistry method of the synthesizing ethoxyquinoline of high yield belongs to the technical field of organic synthesis of biocatalysis.
Background technology
Ethoxyquinoline (6-oxyethyl group-2,2,4-trimethylammonium-1,2-dihydroquinoline, English name Ethoxyquin, molecular formula C
14H
19NO, molecular weight 217.3, CAS numbers 91-53-2, structure See Figure) be a kind of mycocide and feeding antioxidant (LD of high-efficiency low-toxicity low residue
50800mg/kg, only finding has mutagenesis to bacterium and yeast, not finding has mutagenesis to Mammals, also find no carcinogenic and teratogenesis), when being widely used as gathering in the crops in the world and the growth regulator and the mould inhibitor of the apple of duration of storage, pear and other fruits, the colour protecting agent of essence and flavoring agent, and be one of feeding antioxidant of at present safe and effective, the pet, livestock and poultry and the fish that are most widely used.Also promotion and application have widely been obtained at home as one of feed antioxidant safely and effectively.
Chinese patent 03132092.9
[1]And 200510023419.X
[2]Described the synthetic method of general ethoxyquinoline, they are raw material with p-phenetidine and acetone all, by following reaction synthesizing ethoxyquinoline:
P-phenetidine acetone ethoxyquinoline
Reference:
[1] Chinese invention patent: a kind of method of synthesizing ethoxyquinoline (patent No.: 03132092.9)
[2] Chinese invention patent: a kind of production method (patent No.: 200510023419.X) of ethoxyquinoline
Summary of the invention
This patent relates to a kind of eco-friendly, carries out in the mode of biocatalysis, and is relatively inexpensive, the zymochemistry method of the synthesizing ethoxyquinoline of high yield.More unique is, it relates to a kind of improved synthetic route, with synthetic the disassembling of ethoxyquinoline is two steps, at first with biocatalysis technology with isobutyric aldehyde or 4-methyl-2, the 3-diacetylmethane is converted into 3-hydroxy-4-methyl-2 pentanone, dehydration obtains key precursor, 4-methylpentene-3-ketone-2, allow 4-methylpentene-3-ketone-2 and p-phenetidine condensation obtain ethoxyquinoline then, make reaction be tending towards finishing, significantly improved productive rate and degree of purity of production.Operate according to this patent, compare with existing synthetic method, can avoid using concentrated acid, temperature of reaction is greatly reduced, reaction times shortens dramatically, and raw-material transformation efficiency and utilization ratio are greatly improved, and thoroughly eradicates the pollution threat of the production of ethoxyquinoline to environment, the realization environmental friendliness is produced, more than these improvement for the chemosynthesis of the use that relates to environmental pollution and p-phenetidine and so on poisonous and harmful reactant, be vital.
Ethoxyquinoline is known to be a kind of mycocide and feeding antioxidant of high-efficiency low-toxicity low residue, when being widely used as gathering in the crops in the world and the growth regulator and the mould inhibitor of the apple of duration of storage, pear and other fruits, the colour protecting agent of essence and flavoring agent, and be one of feeding antioxidant of at present safe and effective, the pet, livestock and poultry and the fish that are most widely used.Also promotion and application have widely been obtained at home as one of feed antioxidant safely and effectively.
Chinese invention patent 03132092.9 has been described the process improvement, with H
2SO
4-MoO
3-TiO
2Solid super-strong acid is the chemical synthesis process of the ethoxyquinoline of catalyzer.This method is with raw catalyst H
2SO
4-MoO
3-TiO
2Substituting traditional catalyzer sulphuric acid catalysis should reaction, is intended to accelerate the speed of building-up reactions, improves the per pass conversion of building-up reactions, simultaneously, realize catalyzer recycle and reaction mixture need not directly to enter distillation under the neutral condition.
Chinese invention patent 200510023419.X has described a kind of improvement to production method.This method is by changing the solvent in the water trap in the reaction later stage, the one way that realizes p-phenetidine transforms fully, be intended to save rectification step, enhance productivity, the content of the p-phenetidine in the reaction mixture is reduced to below the 1%wt., make reaction mixture just can reach the foodstuff additive standard, sell as product without rectifying.
Before address, above-mentioned two kinds of methods all do not relate to the improvement to reaction raw materials in synthetic, be raw material with p-phenetidine and acetone all.Because the generation of product depends on the generation of gained key intermediate species 4-methylpentene-3-ketone-2 behind the condensation of acetone of two molecules in this building-up reactions, 4-methylpentene-3-ketone-2 is very slow again with the speed of response of p-phenetidine, thereby above-mentioned synthetic method all can't thoroughly be eliminated synthesis reaction temperature height (more than 140 ℃), long reaction time (more than 40 hours), lower boiling reaction raw materials acetone is not high because of too volatile transformation efficiency, for a long time high temperature steaming causes the association of many side reactions that are difficult to expect and explain, cause shortcomings such as the formation of a large amount of waste water and dregs and discharging, still to the threat of environment.
Thereby, one of most important purpose of the present invention, be exactly will with the reaction of p-phenetidine condensation in crucial synthetic precursor, 4-methylpentene-3-ketone-2 substitutes volatile raw material acetone, thereby reduction temperature of reaction, shorten the reaction times, and do not re-use strong acid and make catalyzer, form green, can not cause any dysgenic synthesis technique to environment, realize the environmentally friendly production of ethoxyquinoline.Simultaneously,, the transformation efficiency of p-phenetidine and 4-methylpentene-3-ketone-2 all is largely increased, reduces the production cost of product with this by avoiding side reaction.
As a result along band, another target of the present invention provides a kind of 4-methylpentene-3-ketone-2 in the reaction mixture and content of p-phenetidine of making and reduces to below the 1%wt. simultaneously in pairs, make reaction mixture just can reach content standard more than 95%, the technology of selling as product without rectifying.
Compare with chemical synthesis process, the enzyme-chemically method synthesis technique of ethoxyquinoline has very large superiority.By selecting proper raw material, earlier key intermediate species 4-methylpentene-3-ketone-2 is synthesized with biotransformation method, and then carry out second the step building-up reactions, can avoid using concentrated acid, temperature of reaction is greatly reduced, reaction times shortens dramatically, raw-material transformation efficiency and utilization ratio are greatly improved, the formation and the quantity discharged of waste water and dregs are greatly reduced, thereby overcome the above-mentioned defective of existing chemical synthesis process, this all has very important significance for saving energy and reduce the cost, reduce cost, reduce and eliminate pollution to environment etc.
Specifically, at first, we find, be bonded to precursor with the pass of p-phenetidine condensation, 4-methylpentene-3-ketone-2, be to utilize pyruvic carboxylase (PDC) in the yeast or alcoholdehydrogenase (ADH) easily with isobutyric aldehyde or 4-methyl-2, the 3-diacetylmethane is that material, enzyme method transforms and obtains.The significance of this discovery is, this allows us with as mild as a dove, and eco-friendly mode obtains to close and be bonded to precursor, 4-methylpentene-3-ketone-2.
Also find, the building-up reactions of ethoxyquinoline, when being bonded to precursor with closing, 4-methylpentene-3-ketone-2, substitute acetone after, the temperature of building-up reactions reduces greatly, speed of response is accelerated greatly, to the also greatly reduction of requirement of catalyzer, building-up reactions can quantitatively be finished.
Ethoxyquinoline synthetic thereby be broken down into key precursor, 4-methylpentene-3-ketone-2, biocatalysis transform generate and with two steps of condensation of p-phenetidine.For being to set out for raw material synthetic with isobutyric aldehyde, cereuisiae fermentum is proved to be effective pyruvic carboxylase (PDC) source in practice, and the isobutyric aldehyde acetoin that can successive under 0 ℃ to 40 ℃ temperature stream be added turns to 4-methyl-3-hydroxyl-2 pentanone; For with 4-methyl-2, the 3-diacetylmethane is the synthetic of raw material that set out, bread yeast is proved to be effective alcoholdehydrogenase (ADH) source in practice, the 4-methyl-2 that can successive under 0 ℃ to 40 ℃ temperature stream be added, and the selective reduction of 3-diacetylmethane is 4-methyl-3-hydroxyl-2 pentanone; Which kind of raw material no matter to set out all dehydrated subsequently 4-methylpentene-3-ketone-2 that obtains of gained 4-methyl-3-hydroxyl-2 pentanone with.We find that also the temperature that is lower than 35 ℃ is added the long reaction times, and is higher with temperature, and short method was compared and can be provided higher productive rate the time.Methyl-the needed reaction times of 3-hydroxyl-2 pentanone is 2 to 14 hours to form 4-among the present invention, and it is about 4 to 16 hours that ethoxyquinoline synthetic reaches the preferable time period of finishing substantially.
Isobutyric aldehyde or 4-methyl-2 after the mentioned whole optimizations of all important parameters among the present invention, the transformation efficiency of 3-diacetylmethane and p-phenetidine all can be increased near 100%.
Employed 4-methyl-3-hydroxyl-2 pentanone recovery, dehydration and 4-methylpentene-3-ketone-2 recovery technology is continued to use traditional method substantially among the present invention.After the ethoxyquinoline building-up reactions is finished, reaction mixture is cooled off physical sepn.These steps have provided the good productive rate of chromatographically pure product.
Embodiment
Following example will specify working method of the present invention, but can not be as limitation of the invention.
1, the biological catalysis of 4-methylpentene-3-ketone-2 preparation
Example one
20g sucrose, 0.2g the commercially available bread yeast of Sodium phosphate dibasic and 1g is added in the 150g tap water and constitutes mixture, subsequently under continuous stirring condition, cultivate 15-60min down at 35 ℃, treat that bread yeast enters the vigorous growth after date, with 11.4g 4-methyl-2,3-diacetylmethane liquid adds in the mixture, after 35 ℃ 120min is cultivated in continuation down, and centrifugal (5 ℃, 12000rpm, 30min) remove thalline, fermented liquid is moved in the separating funnel, use equal-volume ethyl acetate extraction three times, the combined ethyl acetate extraction liquid, place water distilling apparatus, add distillating recovering solvent ethyl acetate behind a small amount of zeolite, treat that the solvent recuperation back that finishes adds small amount of solid iodine in water distilling apparatus, continue slowly distillation under the elevated temperature to 133 ℃ subsequently, obtain 9.8g 4-methylpentene-3-ketone-2.
Example two
20g sucrose, 0.2g the commercially available cereuisiae fermentum of Sodium phosphate dibasic and 1g is added in the 150g tap water and constitutes mixture, subsequently under continuous stirring condition, cultivate 15-60min down at 35 ℃, treat that cereuisiae fermentum enters the vigorous growth after date, 7.2g isobutyric aldehyde liquid is added in the mixture, change over to subsequently in the refrigerator, cultivate 480min, centrifugal then (4 ℃ down for 4 ℃, 12000rpm, 30min) remove thalline, fermented liquid is moved in the separating funnel, use equal-volume ethyl acetate extraction three times, the combined ethyl acetate extraction liquid, place water distilling apparatus, add distillating recovering solvent ethyl acetate behind a small amount of zeolite, treat that the solvent recuperation back that finishes adds small amount of solid iodine in water distilling apparatus, continue slowly distillation under the elevated temperature to 133 ℃ subsequently, obtain 9.8g 4-methylpentene-3-ketone-2.
2,4-methylpentene-3-ketone-2 and p-phenetidine condensation synthesizing ethoxyquinoline
In reaction unit, add 9.8g 4-methylpentene-3-ketone-2, the 12.1g p-phenetidine, 30ml toluene is heated to backflow with reaction system subsequently, keeps reaction 8hr.After reaction finishes, the band aqua toluene in the reaction system is reclaimed, obtain ethoxyquinoline 20.1g.
Claims (10)
1. the enzyme-chemical method of a synthesizing ethoxyquinoline.This method is made up of the following step:
(1) with the yeast being biological catalyst, in specific bio-transformation system, is 3-hydroxy-4-methyl-2 pentanone with the substrate bio-transformation.
(2) the bio-transformation system of having finished bio-transformation is carried out separation and Extraction, obtain 3-hydroxy-4-methyl-2 pentanone.
(3) 3-hydroxy-4-methyl-2 pentanone is carried out processed, obtain 4-methylpentene-3-ketone-2.
(4) make 4-methylpentene-3-ketone-2 and p-phenetidine carry out condensation, obtain ethoxyquinoline.
The yeast of being declared means the common yeast kind that can buy on the markets such as bread yeast, cereuisiae fermentum.The substrate of being declared means isobutyric aldehyde or 4-methyl-2, the 3-diacetylmethane.
The bio-transformation system of being declared refers to the mixture that is made of together with yeast water, recuding sugars and phosphoric acid salt.
The bio-transformation of being declared means the bio-transformation system under certain temperature, pressure, utilizes peculiar enzyme system in the yeast, the process of catalytic substrate generation chemical transformation formation reaction product.
The separation and Extraction of being declared is centrifugal, extraction, solvent recuperation etc. obtain pure substance from reaction mixture operating process.
The processed of being declared obtains the process of 4-methylpentene-3-ketone-2 for making 3-hydroxy-4-methyl-2 pentanone generation molecule inner dewatering reaction.
Intermolecular dehydration reaction takes place for making 4-methylpentene-3-ketone-2 and p-phenetidine in the condensation of being declared, obtains the process of ethoxyquinoline.
2. the water system of declaring in the claim 1 refers to that pH regulator is the tap water or the deionized water of certain certain value, and its pH value is within the 2-12 scope.
3. the recuding sugars of declaring in the claim 1 means the utilizable various carbon sources of yeast such as glucose, maltose.
4. the phosphoric acid salt of declaring in the claim 1 means various phosphoric acid salts such as sodium hydrogen phosphate, Sodium phosphate dibasic.
5. the bio-transformation of declaring in the claim 1, its working pressure are 0.0001-0.5MPa.
6. the bio-transformation of declaring in the claim 1, its service temperature are 0-40 ℃.
7. that declares in the claim 1 is centrifugal, and its operational condition is under 0-40 ℃, centrifugal 10-60min under the rotating speed of 3000-20000rpm.
8. the extraction of declaring in the claim 1, its operational condition are under 0-40 ℃, with equal-volume extraction agent extraction 3 times.Used extraction agent can be the various organic solvents that 3-hydroxy-4-methyl-2 pentanone can be extracted from fermented liquid such as ethyl acetate, ether, tertiary butyl methyl ether.
9. the dehydration of declaring in the claim 1, its working pressure are normal pressure, and service temperature is 120-150 ℃.Can add small amount of solid iodine as catalyzer.
10. the condensation of declaring in the claim 1, its working pressure are normal pressure, and service temperature is 80-150 ℃.Can add a small amount of band aqua.Used band aqua can be that benzene, toluene or any other can form azeotropic mixture with water in this temperature range, with water band any other reagent from reaction system.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100385199A CN101275153A (en) | 2007-03-26 | 2007-03-26 | Enzyme-chemical method for synthesizing ethoxyquinoline |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100385199A CN101275153A (en) | 2007-03-26 | 2007-03-26 | Enzyme-chemical method for synthesizing ethoxyquinoline |
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| CN101275153A true CN101275153A (en) | 2008-10-01 |
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| CNA2007100385199A Pending CN101275153A (en) | 2007-03-26 | 2007-03-26 | Enzyme-chemical method for synthesizing ethoxyquinoline |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105001157A (en) * | 2015-07-23 | 2015-10-28 | 泰兴瑞泰化工有限公司 | Method for preparing ethoxy quinoline |
| CN110747241A (en) * | 2018-07-24 | 2020-02-04 | 中国石油化工股份有限公司 | Preparation method of 2,2, 4-trimethyl-1, 2-dihydroquinoline |
-
2007
- 2007-03-26 CN CNA2007100385199A patent/CN101275153A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105001157A (en) * | 2015-07-23 | 2015-10-28 | 泰兴瑞泰化工有限公司 | Method for preparing ethoxy quinoline |
| CN110747241A (en) * | 2018-07-24 | 2020-02-04 | 中国石油化工股份有限公司 | Preparation method of 2,2, 4-trimethyl-1, 2-dihydroquinoline |
| CN110747241B (en) * | 2018-07-24 | 2023-05-02 | 中国石油化工股份有限公司 | Preparation method of 2, 4-trimethyl-1, 2-dihydroquinoline |
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Open date: 20081001 |