CN107556260B - A kind of etoxazole preparation method - Google Patents
A kind of etoxazole preparation method Download PDFInfo
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Abstract
The present invention provides a kind of etoxazole preparation method, the preparation method is that compound shown in Formulas I is reacted with ammonia or ammonia solution generates etoxazole, preparation method simple process of the invention, good reaction selectivity, can be greatly reduced the generation of etoxazole isomer impurities, and reaction yield is up to 87-95%, product content is up to 95-97%, by-product is only ammonium chloride, and content meets the national standard of industrial ammonium chloride up to 99% or more.Meanwhile can avoid introducing the water into reaction system using ammonia or methanolic ammonia solution, to save the rectifying separation process of organic solvent and water in solvent recovery, the cost and energy consumption of production equipment are reduced, industrialized production is suitable for, higher economic benefit can be generated.
Description
Technical field
The invention belongs to agricultural chemical insecticide fields, are related to a kind of etoxazole preparation method.
Background technique
Etoxazole, English name: Etoxazole is a kind of high-efficiency low-toxicity agriculture of Japanese eight continent chemical companies research and development in 1994
With acaricide, the new compound with diphenyloxazole quinoline structure, entitled 4- (4- (the tert-butyl) -2- ethoxybenzene of chemistry
Base) -2- (2,6- difluorophenyl) oxazoline, molecular formula are as follows: C21H23F2NO2, No. CAS are as follows: 153233-91-1；Appearance white is brilliant
Body powder, fusing point: 101-102 DEG C, structural formula is as follows:
Currently, the preparation method of etoxazole is by cyclization in intermediate molecule come CN1024794, US5478855
Two kinds of methods for preparing etoxazole are individually disclosed with EP0639572:
Dehydrating agent in route 1 is usually sulfuric acid, thionyl chloride, phosphorus oxychloride, phosphorus pentoxide, reaction condition requirement
Compare harsh, the three wastes of generation are more, are not suitable for industrialized production.Route 2 uses methanol, ethyl alcohol, N, N'- dimethylformamide
Or dimethyl sulfoxide makees solvent, sodium hydrate aqueous solution, potassium hydroxide or potassium carbonate do alkali and carry out cyclization reaction, mild condition,
By-product is only inorganic salts, be suitble to industrialized production, however this method there is also two o'clock deficiency, first point: due to the O in amide
Atom and N atom all have nucleophilicity, and O atom participates in cyclization and then generates target product etoxazole, and N atom participates in cyclization and then generates
Impurity isomers, US5478855 and EP0639572 disclose the yield only 62.5% of chlorination, cyclization two-step reaction.In addition, mesh
Before have the synthesis of disclosed etoxazole (synthesis of novel acaricide-etoxazole, Dai Weie, Cheng Zhiming, Zhejiang chemical industry, 2009 years the
7-9 pages of the phase of volume 40 the 7th) report in, using 20% sodium hydroxide solution do alkali preparation etoxazole, cyclization step yield be 70%.
Second point: doing alkali using sodium hydrate aqueous solution, then needs to separate methanol and water by rectifying in solvent recovery, production
Equipment cost will be greatly increased with energy consumption.
Therefore, in order to overcome the defect of existing method, need to develop new etoxazole preparation method.
Summary of the invention
In view of the deficiencies of the prior art, the purpose of the present invention is to provide a kind of etoxazole preparation methods.
In order to achieve that object of the invention, the invention adopts the following technical scheme:
The present invention provides a kind of etoxazole preparation method, the preparation method is that compound shown in Formulas I and ammonia or ammonia are molten
Liquid reaction generates etoxazole, and specific reaction equation is as follows:
Such reaction conventional means are cyclization reaction to be carried out using highly basic, and this method breaks through conventional means, using weak base
It being reacted, can reduce the generation of isomers, selective good, high income, product content are high, and by-product only has ammonium chloride, and
And reach the national standard of industrial ammonium chloride, it is suitable for industrialized production.
Preferably, the equivalent of compound shown in the Formulas I relative to 1 equivalent, the ammonia or ammonia solution is 1~10,
Such as it can be 1 equivalent, 2 equivalents, 3 equivalents, 4 equivalents, 5 equivalents, 6 equivalents, 8 equivalents, 9 equivalents or 10 equivalents.
Preferably, the ammonia solution is methanolic ammonia solution or ammonium hydroxide.
Preferably, the solvent of the reaction is methanol, ethyl alcohol, N, one in N'- dimethylformamide or dimethyl sulfoxide
Kind or at least two combination, further preferred methanol and/or ethyl alcohol.
Preferably, the temperature of the reaction is 70~120 DEG C, such as can be 70 DEG C, 80 DEG C, 90 DEG C, 100 DEG C, 110 DEG C
Or 120 DEG C.
Preferably, the time of the reaction be 5~20 hours, such as can be 5 hours, 8 hours, 10 hours, 12 hours,
15 hours, 18 hours or 20 hours.
Preferably, the reaction carries out in autoclave.
Preferably, the pressure of the reaction be 0.1~0.5MPa, such as can be 0.1MPa, 0.2MPa, 0.3MPa,
0.4MPa or 0.5MPa.
As the preferred technical solution of the present invention, etoxazole the preparation method comprises the following steps: Formulas I compound represented is added to height
It presses in kettle, is dissolved with solvent, relative to 1 equivalent formula I compound represented, the ammonia or ammonia solution of 1~10 equivalent is added, 70
~120 DEG C, react 5~20 hours under 0.1~0.5MPa, obtain the etoxazole.
Compared with the existing technology, the invention has the following advantages:
The present invention is reacted using weak base ammonia or ammonia solution, breaches the conventional means reacted with highly basic such as sodium hydroxides,
Very good effect is reached.Good reaction selectivity, can be greatly reduced the generation of isomer impurities, and reaction yield is up to 87-
95%, product content is up to 95-97%, and by-product is only ammonium chloride, and content meets industrial ammonium chloride up to 99% or more
National standard；And it is avoided that again according to ammonia and methanolic ammonia solution and introduces the water into reaction system, to save methanol and water
Rectifying separation process, reduce the cost and energy consumption of production equipment, be suitable for industrialized production.
Detailed description of the invention
Fig. 1 is the etoxazole HPLC spectrogram in the embodiment of the present invention 1.
Fig. 2 is the etoxazole HPLC spectrogram in reference examples 1 of the present invention.
Specific embodiment
The technical scheme of the invention is further explained by means of specific implementation.Those skilled in the art should be bright
, the described embodiments are merely helpful in understanding the present invention, should not be regarded as a specific limitation of the invention.
Etoxazole detection method of content uses high-performance liquid chromatography in the present invention, etoxazole standard items source:
Dr.Ehrenstorfer GmbH.Ammonium chloride detection method of content: GB/T 2946-2008 is referred to.
Embodiment 1
The compound shown in addition 50g (content 97%) starting materials of formulae I in 500mL stainless steel autoclave, 100g anhydrous methanol,
Kettle cover is closed, after opening inlet valve is passed through ammonia 4.2g, valve is closed and is warming up to 90 DEG C, kettle presses 0.2MPa, is stirred to react 8 hours
Afterwards, heat source is removed, is sampled, (condition: 250mm × 4.6mm (i.d) stainless steel column, built-in C18 (5 μm) is controlled in high performance liquid chromatography
Filler；Mobile phase: acetonitrile: water=70:30 (volume ratio)；Flow velocity: 1.0mL/min；Wavelength: 225nm), middle control spectrogram such as Fig. 1
Shown, specific data are as shown in table 1, by liquid chromatography mass joint technology, respectively obtain retention time 20.8min, retain
The compound molecular weight (high resolution mass spectrum) of time 24.3min, data are as shown in table 1.After fully reacting, relief valve is opened, even
Vacuum pump is connect, system pressure 5-10kPa removes vacuum after recycling 50g methanol, is down to 0-5 DEG C of crystallization 1 hour, in the process
There are a large amount of white solids to be precipitated, filter, use 90g toluene and 30g water to dissolve after filter cake drying, after layering, water layer is de- to be done to obtain 6.3g
White solid, as side product sodium chloride, content 99.5%, the weight yield 96.1% of ammonium chloride；Organic layer obtains after toluene is evaporated off
40.5g etoxazole white solid, content 97%, etoxazole weight yield 92%.
Table 1
| Peak number | Retention time | Chemical combination name | HRMS[M+H]+ | Normalizing area/% |
| 1 | 20.8min | Isomers | 360.1753 | 1.0 |
| 2 | 24.3min | Etoxazole | 360.1754 | 96.7 |
Embodiment 2
The compound shown in addition 50g (content 97%) starting materials of formulae I in 500mL stainless steel autoclave, 150g dehydrated alcohol,
Kettle cover is closed, after opening inlet valve is passed through ammonia 6.2g, valve is closed and is warming up to 80 DEG C, kettle pressure 0.1MPa is stirred to react 7 hours
Afterwards, heat source is removed, is sampled, is controlled in high performance liquid chromatography, the normalizing area 1.2% of isomers, etoxazole normalizing area 96%.To
It after reaction solution is down to 60 DEG C, filters while hot, filter cake dries to obtain 6g white solid, as side product sodium chloride, content 99.3%, chlorination
The weight yield 91.6% of ammonium.Filtrate decompression distillation, system pressure 5-10kPa remove vacuum after recycling 100g ethyl alcohol, in kettle
Concentrate is cooled to 0-5 DEG C and crystallizes 1 hour, has a large amount of white solids to be precipitated in the process, and filtering, filter cake dry to obtain 40.1g
Etoxazole white solid, content 96%, etoxazole weight yield 91%.
Embodiment 3
Compound shown in 50g (content 97%) starting materials of formulae I, 120g N, N'- bis- are added in 500mL stainless steel autoclave
Methylformamide closes kettle cover, after opening inlet valve is passed through ammonia 2.1g, closes valve and is warming up to 70 DEG C, nitrogen ftercompction is extremely
0.4MPa after being stirred to react 20 hours, removes heat source, sampling, controls in high performance liquid chromatography, the normalizing area 0.7% of isomers,
Etoxazole normalizing area 93%.Relief valve is opened, vacuum pump, system pressure 1-3kPa, vacuum distillation recovered solvent, in kettle are connected
90g toluene is added in residue and 30g water dissolves, and after layering, water layer is de- to do to obtain 5.9g white solid, as side product sodium chloride, contains
Amount 99.1%, the weight yield 90% of ammonium chloride；After 45g toluene is evaporated off in organic layer, it is cooled to 0-5 DEG C and crystallizes to obtain 38.3g solid,
Content is 95%, etoxazole weight yield 87%.
Embodiment 4
Compound shown in 50g (content 97%) starting materials of formulae I is added in 500mL stainless steel autoclave, 200g dimethyl is sub-
Sulfone closes kettle cover, after opening inlet valve is passed through ammonia 10.4g, closes valve and is warming up to 120 DEG C, nitrogen ftercompction to 0.3MPa is stirred
After mixing reaction 5 hours, heat source is removed, is sampled, is controlled in high performance liquid chromatography, the normalizing area 1.1% of isomers, etoxazole normalizing
Area 96%.Relief valve is opened, connects vacuum pump, system pressure 1-3kPa, vacuum distillation recovered solvent, residue is added in kettle
90g toluene and 30g water dissolve, and after layering, water layer is de- to do to obtain 6.1g white solid, as side product sodium chloride, content 99.5%, chlorine
Change the weight yield 93% of ammonium；After 45g toluene is evaporated off in organic layer, it is cooled to 0-5 DEG C and crystallizes to obtain 41g solid, content 96%, second
Mite azoles weight yield 93%.
Embodiment 5
(1) preparation of methanolic ammonia solution
In 500mL there-necked flask, 200g anhydrous methanol is added, is put into 0 DEG C of bath, wait be down to 5 DEG C, starts to be passed through under liquid
Ammonia.To get the methanol solution of ammonia after 2 hours, calculating ammonia in the concentration of methanol solution by weightening finish method is 16% (weight hundred
Divide ratio).
(2) preparation of etoxazole
Compound shown in 50g (content 97%) starting materials of formulae I, the above-mentioned ammonia first of 130g are added in 500mL stainless steel autoclave
Alcoholic solution closes valve and is warming up to 100 DEG C, and kettle presses 0.2MPa, after being stirred to react 13 hours, removes heat source, samples, efficient liquid phase
It is controlled in chromatography, the normalizing area 1.0% of isomers, etoxazole normalizing area 97%.Relief valve is opened, vacuum pump, system are connected
Pressure 5-10kPa removes vacuum after recycling 60g methanol, continues to be down to 0-5 DEG C of crystallization 1 hour, has in the process a large amount of white
Color solid is precipitated, and filters, uses 90g toluene and 30g water to dissolve after filter cake drying, and after layering, water layer is de- to be done to obtain 6.2g white solid,
As side product sodium chloride, content 99.6%, the weight yield 95% of ammonium chloride；Organic layer obtains 41.4g etoxazole after toluene is evaporated off
White solid, content 97%, etoxazole weight yield 94%.
Embodiment 6
Compound shown in 50g (content 97%) starting materials of formulae I, 150g methanol, 66g are added in 500mL stainless steel autoclave
Ammonium hydroxide (content 25%) closes valve and is warming up to 110 DEG C, and kettle presses 0.5MPa, after being stirred to react 16 hours, removes heat source, samples,
It is controlled in high performance liquid chromatography, the normalizing area 1.1% of isomers, etoxazole normalizing area 96%.Continue to be cooled to 5-10 DEG C of knot
It is 1 hour brilliant, there are a large amount of white solids to be precipitated in the process, after filtering, filter cake are eluted twice with water, dries to obtain 41.8g second mite
Azoles white solid, content 95%, etoxazole weight yield 95%.Filtrate air-distillation, after gas phase temperature reaches 100 DEG C,
Stop distillation, a small amount of etoxazole of 10g toluene extraction and recovery is added, remaining water layer is de- to do to obtain 6g white solid, as by-product chlorine
Change ammonium, content 99.1%, the weight yield 91.6% of ammonium chloride
Reference examples 1
The compound shown in addition 40.2g (content 97%) starting materials of formulae I in 500mL there-necked flask, 158g anhydrous methanol, then
It is slowly dropped into the sodium hydrate aqueous solution that 85g mass concentration is 20%, mixture after finishing is dripped and is warming up to 70 DEG C, it is small to be stirred to react 1
When, (condition: 250mm × 4.6mm (i.d) stainless steel column, built-in C18 (5 μm) filler is controlled in HPLC；Mobile phase: acetonitrile: water
=70:30 (volume ratio)；Flow velocity: 1.0mL/min；Wavelength: 225nm), high performance liquid chromatography spectrogram is shown in Fig. 2, specific data such as table
Shown in 2, by liquid chromatography mass joint technology, the chemical combination of retention time 22.2min, retention time 26.4min are respectively obtained
Object molecular weight (high resolution mass spectrum), data are as shown in table 2.Methanol and water mixed solution are recycled in vacuum distillation, and residue adds in kettle
Enter 75g toluene and 30g water dissolves, after layering, after 40g toluene is evaporated off in organic layer, is cooled to 0-5 DEG C and crystallizes to obtain 27.3g solid, contain
Amount is 95%, etoxazole weight yield 77%.
Table 2
Comparative example 1 and reference examples 1, it can be deduced that conclusion be to be prepared using preparation method of the invention
Etoxazole yield and content are higher, inhibit isomer impurities effect clearly, and are prepared using NaOH aqua-solution method
Etoxazole yield it is low, and isomer impurities are more.Therefore preparation method of the invention has high excellent of high income, content
Point is suitable for industrialized production.
The Applicant declares that a kind of the present invention is explained by the above embodiments etoxazole preparation method of the invention, but this
Invention is not limited to above-mentioned processing step, that is, does not mean that the present invention must rely on the above process steps to be carried out.It is affiliated
Those skilled in the art it will be clearly understood that any improvement in the present invention, equivalence replacement to raw material selected by the present invention and
Addition, selection of concrete mode of auxiliary element etc., all of which fall within the scope of protection and disclosure of the present invention.
Claims (9)
1. a kind of etoxazole preparation method, which is characterized in that the preparation method is that: compound shown in Formulas I and ammonia or ammonia are molten
Liquid reaction generates etoxazole, and specific reaction equation is as follows:
The equivalent of compound shown in the Formulas I relative to 1 equivalent, the ammonia or ammonia solution is 1~10.
2. etoxazole preparation method according to claim 1, which is characterized in that the ammonia solution is methanolic ammonia solution or ammonia
Water.
3. etoxazole preparation method according to claim 1, which is characterized in that the solvent of the reaction be methanol, ethyl alcohol,
One of N, N'- dimethylformamide or dimethyl sulfoxide or at least two combination.
4. etoxazole preparation method according to claim 3, which is characterized in that the solvent of the reaction be methanol and/or
Ethyl alcohol.
5. etoxazole preparation method according to claim 1, which is characterized in that the temperature of the reaction is 70~120 DEG C.
6. etoxazole preparation method according to claim 1, which is characterized in that the time of the reaction is 5~20 hours.
7. etoxazole preparation method according to claim 1, which is characterized in that the reaction carries out in autoclave.
8. etoxazole preparation method according to claim 1, which is characterized in that the pressure of the reaction be 0.1~
0.5MPa。
9. etoxazole preparation method according to claim 1 to 8, which is characterized in that the preparation method is that:
Formulas I compound represented is added in autoclave, is dissolved with solvent, relative to 1 equivalent formula I compound represented, it is added 1~
The ammonia or ammonia solution of 10 equivalents react 5~20 hours at 70~120 DEG C, 0.1~0.5MPa, obtain the etoxazole.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1318536A (en) * | 1994-08-12 | 2001-10-24 | 拜尔公司 | Substituted biphenyl oxazoline |
| CN1205195C (en) * | 1997-03-05 | 2005-06-08 | 拜尔公司 | Disubstituted biphexyloxazolines |
| CN103113318A (en) * | 2013-02-26 | 2013-05-22 | 南京工业大学 | New etoxazole compound, preparation method and acaricidal activity thereof |
-
2017
- 2017-10-20 CN CN201710982780.8A patent/CN107556260B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1318536A (en) * | 1994-08-12 | 2001-10-24 | 拜尔公司 | Substituted biphenyl oxazoline |
| CN1205195C (en) * | 1997-03-05 | 2005-06-08 | 拜尔公司 | Disubstituted biphexyloxazolines |
| CN103113318A (en) * | 2013-02-26 | 2013-05-22 | 南京工业大学 | New etoxazole compound, preparation method and acaricidal activity thereof |
Non-Patent Citations (3)
| Title |
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| Synthesis of m-Alkylphenols via a Ruthenium-Catalyzed C-H Bond Functionalization of Phenol Derivatives;Gang Li et al.;《Org. Lett.》;20170508;第19卷;第2682-2685页 |
| 乙螨唑的合成工艺;丁成荣 等;《农药》;20141031;第53卷(第10期);第715-717页 |
| 新颖杀螨剂--螨唑的合成;戴炜锷 等;《浙江化工》;20091231;第40卷(第7期);第7-9页 |
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