CN109232470A - A kind of new process synthesizing ainothiazoly loximate - Google Patents
A kind of new process synthesizing ainothiazoly loximate Download PDFInfo
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- CN109232470A CN109232470A CN201810951904.0A CN201810951904A CN109232470A CN 109232470 A CN109232470 A CN 109232470A CN 201810951904 A CN201810951904 A CN 201810951904A CN 109232470 A CN109232470 A CN 109232470A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom
- C07D277/593—Z being doubly bound oxygen or doubly bound nitrogen, which nitrogen is part of a possibly substituted oximino radical
Abstract
The invention belongs to medicine intermediate synthesis technical fields, and in particular to a kind of new process for synthesizing ainothiazoly loximate.The technique include oximate, hydrocarbonylation, chlorination, cyclization, hydrolysis and the purification under acid condition and etc. synthesize medicine intermediate ainothiazoly loximate sterling.The technological operation is simple, is easily achieved, and overall reaction mass yield reaches 95.8% or more, 99.7% or more purity；The reaction process generation three wastes are relatively fewer, and the burden of later period three-protection design is smaller, is conducive to industrialized realization, has far-reaching significance to the development of pharmaceuticals industry.
Description
Technical field
The invention belongs to medicine intermediate synthesis technical fields, and in particular to a kind of new process for synthesizing ainothiazoly loximate.
Background technique
Ainothiazoly loximate is a kind of important medicine intermediate, crystalline powder white or yellowish or acicular crystal, main use
It is the side chain of Cefotaxime Sodium, ceftriaxone, Ceftazidime etc. in synthesis cephalosporins preparation.This antibiosis
Plain preparation is the very strong antibiotics production drug of antimicrbial power to grow up external nineteen seventies, at present such antibiosis
The worldwide sales of element still account for 35% or more of entire antibiotic medicine.Ainothiazoly loximate conduct synthesizes third generation cephalosporin
The raw material of cephaloridnum, it is effective to infection caused by some drug-fast bacterias and pathogen difficult to control, and toxicity is lower, curative effect is held
Long, curative effect decades of times higher than penicillin, such drug all compare situation of selling well on international, domestic market at present.Use cefotaxime
Acid cephalosporins medicine principal item have Cefpodoxime, cefotaxime, cefodizime, cefotaxime azoles, thiadiazole cephalosporin,
Cefixime, ceftriaxone, aminosulfa cephalosporins, Ceftiolene, pyridazine cephalosporins and Cefpirome etc., and also
Many new varieties are being continuously available development and application.China's ainothiazoly loximate is given in the extensive use in pharmaceuticals industry of cephalosporin
The pharmaceuticals industry such as intermediate brings huge business opportunity.
The synthesis technology of traditional ainothiazoly loximate can be divided by the difference of raw material and synthesis technology: methyl acetoacetate method,
Ethyl acetoac etate process, chloracetyl acetin method；It is raw material by oxime that wherein ethyl acetoac etate process, which is using ethyl acetoacetate,
Change, etherificate, bromination, cyclization, hydrolysis, purification and etc. preparation；Three second 3.5t are consumed using conventionally produced ainothiazoly loximate, it should
The production safety coefficient of technique is relatively low, also wastes raw material, and high production cost, product quality are not able to satisfy existing market and need
It asks；Production technology hardly results in popularization, is difficult to adapt to the present market competitiveness.
A kind of synthetic method of ainothiazoly loximate is disclosed in patent 201010149423.1, oximation reaction is made using glacial acetic acid
For acidizing reagent, higher cost；Chlorinating step uses triphosgene as chlorinating agent, and triphosgene is readily decomposed to as hypertoxic phosgene,
Risk is larger, and triphosgene is needed to prepare in advance and is added dropwise as solution form, complex steps；Cyclization uses sodium acetate
As buffer salt, waste water containing acetate is tacky in subsequent treatment process, and processing cost is larger.
Summary of the invention
To solve the above problems, there is synthesis side the object of the present invention is to provide a kind of new process for synthesizing ainothiazoly loximate
Method is simple, be easily achieved, be at low cost, generation wastewater flow rate is small, later period wastewater treatment burden is small and is advantageously implemented industrialized
Advantage.
The new process of synthesis ainothiazoly loximate of the present invention, comprising the following steps:
(1) acetic acid acetyl triethyl and sodium nitrite are added to the water, sulfuric acid is added dropwise, is kept the temperature after being added dropwise, uses chloroform
Organic phase is collected in extraction；
(2) organic phase that sodium carbonate and step (1) obtain is added to the water, under the action of phase transfer catalyst, drop
Add dimethyl suflfate, carry out alkylation reaction, keep the temperature, extracted again with chloroform after completion of the reaction, collects organic phase；
(3) processing is dried and dehydrated in the organic phase that step (2) obtains, chlorination catalyst and auxiliary agent is added, is passed through chlorine
Gas carries out chlorination reaction, and after reaction, heat preservation, distillation obtains chloride；Wherein, the auxiliary agent is sodium sulfite or sulfurous acid
Hydrogen sodium；
(4) thiocarbamide is added in methanol aqueous solution, under the action of phase transfer catalyst and surfactant, at the uniform velocity
Chloride is added dropwise in batches, and sodium carbonate is added, controls the pH=4.5-5.5 of reaction, is added dropwise, keeps the temperature, obtains ainothiazoly loximate
Methyl esters；
(5) ainothiazoly loximate methyl esters is put into water, 30% liquid alkaline is added dropwise, active carbon decoloring is added, adjusts acid, obtains ammonia
Thiophene oxime acid crude；
(6) ainothiazoly loximate crude product is refined using methanol eddy, obtains ainothiazoly loximate.
Wherein:
In step (1), temperature is controlled in 10-20 DEG C of dropwise addition sulfuric acid.
In step (2), the temperature of alkylation reaction is 13-20 DEG C.
In step (2), phase transfer catalyst is polyethers chain polyethylene glycol, benzyltriethylammoinium chloride (TEBA), four fourths
Base ammonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate (TBAB), tri-n-octyl methyl ammonium chloride, trimethyl chlorine
Change ammonium, tetradecyl trimethyl ammonium chloride tetramethyl ammonium chloride, hexadecyltrimethylammonium chloride or cetyl trimethyl bromine
Change one or more of ammonium；The dosage of phase transfer catalyst is the 0.76-0.78% for the organic phase quality that step (1) obtains.
In step (3), chlorination catalyst is the mixture of the concentrated sulfuric acid and methanol, and the weight ratio of the concentrated sulfuric acid and methanol is 1-
1.5:8, chlorination catalyst weight are the 1-5.5% for the organic phase weight that step (2) obtain.
In step (4), in methanol aqueous solution, the mass ratio of methanol and water is 13:1, and dropping temperature is at 20-30 DEG C.
In step (4), phase transfer catalyst is polyethers chain polyethylene glycol, benzyltriethylammoinium chloride (TEBA), four fourths
Base ammonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate (TBAB), tri-n-octyl methyl ammonium chloride, trimethyl chlorine
Change ammonium, tetradecyl trimethyl ammonium chloride tetramethyl ammonium chloride, hexadecyltrimethylammonium chloride or cetyl trimethyl bromine
Change one or more of ammonium, the weight of phase transfer catalyst is the 0.5-1.4% that chloride weight is added dropwise.
In step (4), surfactant is ionic surfactant or nonionic surface active agent.
In step (4), sodium carbonate is added using solid charger, and control temperature is reacted at 22-28 DEG C.
In step (5), ainothiazoly loximate methyl esters is put into the water of 3 times of quality, and 30% liquid of 0.8 times of quality is added dropwise
Active carbon decoloring is added after dissolved clarification in alkali, first with hydrochloric acid tune pH=7, after decoloration, and through toning acid to pH=2.5-3.0,
Obtain ainothiazoly loximate crude product.
As a kind of perferred technical scheme, the new process of synthesis ainothiazoly loximate of the present invention, specifically includes following
Step:
(1) sodium nitrite and ethyl acetoacetate are added to the water, control 10-20 DEG C of temperature, sulfuric acid is added dropwise, drips
Finish, heat preservation is extracted, liquid separation with chloroform, collects organic phase；
(2) organic phase that soda ash and step (1) obtain is added to the water, controls 13-20 DEG C of temperature, then urge in phase transfer
Under the action of agent, dimethyl suflfate is added dropwise, end of reaction is extracted with chloroform, collects organic phase；
(3) it is carried out dehydrating to the organic phase that step (2) obtains, while under the action of catalyst and auxiliary agent, being passed through
Chlorine carries out chlorination, and chloride is obtained after distillation；
(4) thiocarbamide is added in cyclization mother liquid, phase transfer catalyst and auxiliary agent is added, a dropping step (3) obtains thereto
The chloride arrived is reacted at 22-28 DEG C of temperature of control, is kept the temperature after completion of the reaction at 32-36 DEG C with powdered sodium carbonate buffer salt,
Duration 2h adjusts pH to 4.5-5.5, obtains ainothiazoly loximate methyl esters；
(5) the ainothiazoly loximate methyl esters that step (4) obtains is put into water, rises to 50 DEG C to temperature and starts that liquid alkaline is added dropwise,
Active carbon decoloring is added, destainer hydrochloric acid tune pH to 3 obtains ainothiazoly loximate crude product；
(6) the ainothiazoly loximate crude product refining methanol for obtaining step (5), obtains ainothiazoly loximate product.
The cyclization mother liquid is methanol aqueous solution.
It is according to the present invention using phase transfer catalyst and chlorine gas selecting it is relatively weak under the influence of produce ammonia
The method of thiophene oxime acid just makes up the deficiency of existing traditional handicraft.
Compared with prior art, beneficial effects of the present invention are as follows:
1, synthetic method of the present invention is at low cost, and three wastes yield is relatively low, and the burden of later period three-protection design is smaller, favorably
In industrialized production.
2, synthetic method craft of the present invention is simple, easily operated, and equipment requirement is lower compared with bromine technique, overall reaction matter
Amount yield reaches 95.8% or more, 99.7% or more purity.
3, oximation reaction of the present invention is using sulfuric acid as acidizing reagent, and cost is relatively low.
4, the present invention is used as chlorinating agent using chlorine, low in cost, can be passed directly in methide, it is simple just
Just, easily operated, while overcoming the disadvantage that chlorination reaction poor selectivity, yield are low, initiation is difficult.
5, cyclization process of the present invention uses phase transfer catalyst and surfactant, improves the selectivity of chloride,
While controlling oily mater generation, yield is improved.
6, cyclization process of the present invention uses sodium carbonate as buffer salt, and low in cost, the later period, easy process viscosity was low, processing
It is easy.
Specific embodiment
The present invention is described further with reference to embodiments.
Raw material used in the examples is unless otherwise specified marketable material.
Embodiment 1
(1) it is added in 1000mL three-necked flask and sequentially adds 348g water, 50g sodium nitrite, 88g acetic acid acetyl triethyl,
98% concentrated sulfuric acid 38.5g, used time 1.2h is added dropwise in 18 DEG C of temperature of control, after keeping the temperature 1h, is layered to it, to water phase chlorine
It is imitative to be extracted, organic phase is merged, organic phase 263g is obtained；
(2) alkali tune is carried out to the waste water that step (1) obtains, makes its pH=7, with 25g sodium hydroxide, 50g sodium carbonate is added
With organic phase obtained in upper step, tetrabutylammonium chloride 2.0g is added, controls 15-18 DEG C of temperature, dimethyl suflfate 120g is added dropwise,
90min is added dropwise, temperature-resistant insulation reaction 60min, is warming up to 48-50 DEG C of heat preservation 60min, is extracted with chloroform, collection has
Machine phase 330g；
(3) organic phase for obtaining step (2) is added after 22.8g anhydrous calcium chloride powder is dehydrated and filters, to primary
16.5g anhydrous calcium chloride is added in dehydration filtrate to carry out second filtering after being dehydrated, then into second of dewatered filtrate
The mixture of the 3g concentrated sulfuric acid and 15g methanol is added, sodium sulfite 1.0g starts to be passed through chlorine, stops being passed through chlorine after the 84g that ventilates
Gas, decompression boil off solvent, obtain chloride 145g；
(4) thiocarbamide 50g is added in the mixed liquor of 140g first alcohol and water, 1.0g sodium sulfite, cetyl three is added
Methyl bromide ammonium 1.5g starts that powdered sodium carbonate 30g is added dropwise, while the chloride that a dropping step (3) obtains, 2h are dripped off, control
22-28 DEG C of temperature, the reaction was continued 2.5h, pH to 5 is adjusted, ainothiazoly loximate methyl esters is precipitated；Wherein, sodium carbonate uses solid charger
It is added；
(5) the ainothiazoly loximate methyl esters that step (4) obtains is put into 300g water, starts dropwise addition 0.8 after being warming up to 55 DEG C
After dissolved clarification, 2g activity carbon decoloring is added in 30% liquid alkaline of times quality, and destainer is first with hydrochloric acid tune pH=7, after decoloration,
With hydrochloric acid tune pH to 3, ainothiazoly loximate crude product is obtained；
(6) ainothiazoly loximate crude product is put into first low temperature in the methanol of 2 times of volumes and stirs 2h, then high temperature reflux 4h, cooling analysis
Crystalline substance dries to obtain ainothiazoly loximate, overall reaction mass yield 96.3%, purity 99.7%.
Embodiment 2
(1) it is added in 1000mL three-necked flask and sequentially adds 348g water, 50g sodium nitrite, 88g acetic acid acetyl triethyl,
98% concentrated sulfuric acid 38.5g, used time 1.2h is added dropwise in 20 DEG C of temperature of control, after keeping the temperature 1h, is layered to it, to water phase chlorine
It is imitative to be extracted, organic phase is merged, organic phase 260g is obtained；
(2) alkali tune is carried out to the waste water that step (1) obtains, makes its pH=7, with 25g sodium hydroxide, 50g sodium carbonate is added
With organic phase obtained in upper step, tetrabutylammonium bromide 2.0g is added, controls 15-18 DEG C of temperature, dimethyl suflfate 120g is added dropwise,
90min is added dropwise, temperature-resistant insulation reaction 60min, is warming up to 48-50 DEG C of heat preservation 60min, is extracted with chloroform, collection has
Machine phase 328g；
(3) organic phase for obtaining step (2), after dehydration, after addition 23.3g anhydrous calcium chloride powder is dehydrated
16.7g anhydrous calcium chloride is added into primary dewatering filtrate and carries out second filtering after being dehydrated, 1g sulfuric acid and 6g first is added for filtering
Sodium sulfite 0.5g is added in the mixture of alcohol, starts to be passed through chlorine, stops being passed through chlorine after the 82g that ventilates, decompression boils off solvent
Afterwards, chloride 149g is obtained；
(4) thiocarbamide 50g is added in the mixed liquor of 140g first alcohol and water, 1g sodium sulfite, cetyl front three is added
Base ammonium bromide 1.5g starts that powdered sodium carbonate 30g is added dropwise, while the chloride that a dropping step (3) obtains, 2h are dripped off, control temperature
22-28 DEG C, the reaction was continued 2.5h of degree, pH to 5 is adjusted, ainothiazoly loximate methyl esters is precipitated；Wherein, sodium carbonate is added using solid charger
Enter；
(5) the ainothiazoly loximate methyl esters that step (4) obtains is put into 300g water, starts dropwise addition 0.8 after being warming up to 54 DEG C
After dissolved clarification, 2g activity carbon decoloring is added in 30% liquid alkaline of times quality, and destainer is first with hydrochloric acid tune pH=7, after decoloration,
With hydrochloric acid tune pH to 3, ainothiazoly loximate crude product is obtained；
(6) ainothiazoly loximate crude product is put into first low temperature in the methanol of 3.2 times of volumes and stirs 2h, then high temperature reflux 4h, it is cooling
Crystallization dries to obtain ainothiazoly loximate, overall reaction mass yield 95.8%, purity 99.75%.
Embodiment 3
(1) it is added in 1000mL three-necked flask and sequentially adds 348g water, 50g sodium nitrite, 88g acetic acid acetyl triethyl,
98% concentrated sulfuric acid 38.5g, used time 1.2h is added dropwise in 18 DEG C of temperature of control, after keeping the temperature 1h, is layered to it, to water phase chlorine
It is imitative to be extracted, organic phase is merged, organic phase 258g is obtained；
(2) alkali tune is carried out to the waste water that step (1) obtains, makes its pH=7, with 25g sodium hydroxide, 50g sodium carbonate is added
With organic phase obtained in upper step, benzyltrimethylammonium chloride 2.0g is added, controls 15-18 DEG C of temperature, dimethyl suflfate is added dropwise
118g, 90min are added dropwise, temperature-resistant insulation reaction 60min, are warming up to 48-50 DEG C of heat preservation 60min, are extracted with chloroform, receive
Collect organic phase 332g；
(3) organic phase that will be obtained is added after 23g anhydrous calcium chloride powder is dehydrated and filters after dehydration, Xiang Yi
16.5g anhydrous calcium chloride is added in secondary dehydration filtrate to carry out second filtering after being dehydrated, then to second of dewatered filtrate
The middle mixture that the 1.0g concentrated sulfuric acid and 8.0g methanol is added, is added sodium hydrogensulfite 0.5g, starts to be passed through chlorine, after the 80g that ventilates
Stopping is passed through chlorine, and decompression obtains chloride 151g after boiling off solvent；
(4) thiocarbamide 50g is added in the mixed liquor of 140g first alcohol and water, 1g sodium sulfite, cetyl front three is added
Ammonium chloride 2.0g starts that powdered sodium carbonate 40g is added dropwise, while the chloride that a dropping step (3) obtains, 2h are dripped off, control temperature
22-28 DEG C, the reaction was continued 2.5h of degree, pH to 5 is adjusted, ainothiazoly loximate methyl esters is precipitated；Wherein, sodium carbonate is added using solid charger
Enter；
(5) the ainothiazoly loximate methyl esters that step (4) obtains is put into 400g water, starts dropwise addition 0.8 after being warming up to 52 DEG C
After dissolved clarification, 2g activity carbon decoloring is added in 30% liquid alkaline of times quality, and destainer is first with hydrochloric acid tune pH=7, after decoloration,
With hydrochloric acid tune pH to 2.6, ainothiazoly loximate crude product is obtained；
(6) ainothiazoly loximate crude product is put into first low temperature in the methanol of 2.95 times of volumes and stirs 2h, then high temperature reflux 4h, it is cooling
Crystallization dries to obtain ainothiazoly loximate, overall reaction mass yield 96.0%, purity 99.7%.
Claims (10)
1. a kind of new process for synthesizing ainothiazoly loximate, it is characterised in that: the following steps are included:
(1) acetic acid acetyl triethyl and sodium nitrite are added to the water, sulfuric acid are added dropwise, keeps the temperature after being added dropwise, is extracted with chloroform,
Collect organic phase；
(2) organic phase that sodium carbonate and step (1) obtain is added to the water, under the action of phase transfer catalyst, sulphur is added dropwise
Dimethyl phthalate carries out alkylation reaction, keeps the temperature, extracted again with chloroform after completion of the reaction, collects organic phase；
(3) organic phase that step (2) obtains is dried and dehydrated processing, chlorination catalyst and auxiliary agent is added, be passed through chlorine into
Row chlorination reaction, after reaction, heat preservation, distillation obtain chloride；Wherein, the auxiliary agent is sodium sulfite or bisulfite
Sodium；
(4) thiocarbamide is added in methanol aqueous solution, under the action of phase transfer catalyst and surfactant, at the uniform velocity in batches
Chloride is added dropwise, and sodium carbonate is added, controls the pH=4.5-5.5 of reaction, is added dropwise, keeps the temperature, obtains ainothiazoly loximate methyl esters；
(5) ainothiazoly loximate methyl esters is put into water, 30% liquid alkaline is added dropwise, active carbon decoloring is added, adjusts acid, obtains cefotaxime
Acid crude；
(6) ainothiazoly loximate crude product is refined using methanol eddy, obtains ainothiazoly loximate.
2. the new process of synthesis ainothiazoly loximate according to claim 1, it is characterised in that: in step (1), control temperature exists
10-20 DEG C of dropwise addition sulfuric acid.
3. the new process of synthesis ainothiazoly loximate according to claim 1, it is characterised in that: in step (2), alkylation reaction
Temperature is 13-20 DEG C.
4. the new process of synthesis ainothiazoly loximate according to claim 1, it is characterised in that: in step (2), phase transfer catalysis (PTC)
Agent is polyethers chain polyethylene glycol, benzyltriethylammoinium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutyl hydrogen sulfate
Ammonium, tri-n-octyl methyl ammonium chloride, dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride tetramethyl ammonium chloride, ten
One or more of six alkyl trimethyl ammonium chlorides or cetyl trimethylammonium bromide；The dosage of phase transfer catalyst is step
Suddenly the 0.76-0.78% for the organic phase quality that (1) obtains.
5. the new process of synthesis ainothiazoly loximate according to claim 1, it is characterised in that: in step (3), chlorination catalyst
It is the mixture of the concentrated sulfuric acid and methanol, the weight ratio of the concentrated sulfuric acid and methanol is 1-1.5:8, and chlorination catalyst weight is step
(2) 1-5.5% of the organic phase weight obtained.
6. the new process of synthesis ainothiazoly loximate according to claim 1, it is characterised in that: in step (4), methanol aqueous solution
In, the mass ratio of methanol and water is 13:1, and dropping temperature is at 20-30 DEG C.
7. the new process of synthesis ainothiazoly loximate according to claim 1, it is characterised in that: in step (4), phase transfer catalysis (PTC)
Agent is polyethers chain polyethylene glycol, benzyltriethylammoinium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutyl hydrogen sulfate
Ammonium, tri-n-octyl methyl ammonium chloride, dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride tetramethyl ammonium chloride, ten
One or more of six alkyl trimethyl ammonium chlorides or cetyl trimethylammonium bromide, the weight of phase transfer catalyst are drop
The 0.5-1.4% of chlorination compound weight.
8. the new process of synthesis ainothiazoly loximate according to claim 1, it is characterised in that: in step (4), surfactant
For ionic surfactant or nonionic surface active agent.
9. the new process of synthesis ainothiazoly loximate according to claim 1, it is characterised in that: in step (4), sodium carbonate is used
Solid charger is added, and control temperature is reacted at 22-28 DEG C.
10. the new process of synthesis ainothiazoly loximate according to claim 1, it is characterised in that: in step (5), by cefotaxime
Sour methyl esters is put into the water of 3 times of quality, and 30% liquid alkaline of 0.8 times of quality is added dropwise, and after dissolved clarification, it is de- that active carbon is added
Color after decoloration, through toning acid to pH=2.5-3.0, obtains ainothiazoly loximate crude product first with hydrochloric acid tune pH=7.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111548323A (en) * | 2020-05-29 | 2020-08-18 | 山东金城医药化工有限公司 | Recovery method of aminothiazoly loximate |
| CN111925300A (en) * | 2020-08-12 | 2020-11-13 | 上海应用技术大学 | Synthesis method and device of 4-chloro-2-methoxyimino ethyl acetoacetate |
| CN111978205A (en) * | 2020-08-12 | 2020-11-24 | 上海应用技术大学 | Method and device for continuously synthesizing 4-chloro-2-methoxyimino ethyl acetoacetate |
| CN112010776A (en) * | 2020-08-12 | 2020-12-01 | 上海应用技术大学 | Method and device for continuously synthesizing 4-chloro-2-methoxyimino ethyl acetoacetate |
-
2018
- 2018-08-21 CN CN201810951904.0A patent/CN109232470A/en not_active Withdrawn
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111548323A (en) * | 2020-05-29 | 2020-08-18 | 山东金城医药化工有限公司 | Recovery method of aminothiazoly loximate |
| CN111548323B (en) * | 2020-05-29 | 2022-06-10 | 山东金城医药化工有限公司 | Recovery method of aminothiazoly loximate |
| CN111925300A (en) * | 2020-08-12 | 2020-11-13 | 上海应用技术大学 | Synthesis method and device of 4-chloro-2-methoxyimino ethyl acetoacetate |
| CN111978205A (en) * | 2020-08-12 | 2020-11-24 | 上海应用技术大学 | Method and device for continuously synthesizing 4-chloro-2-methoxyimino ethyl acetoacetate |
| CN112010776A (en) * | 2020-08-12 | 2020-12-01 | 上海应用技术大学 | Method and device for continuously synthesizing 4-chloro-2-methoxyimino ethyl acetoacetate |
| CN111925300B (en) * | 2020-08-12 | 2022-10-14 | 上海应用技术大学 | Synthesis method and device of 4-chloro-2-methoxyimino ethyl acetoacetate |
| CN112010776B (en) * | 2020-08-12 | 2023-04-28 | 上海应用技术大学 | Method and device for continuously synthesizing 4-chloro-2-methoxyiminoacetoacetic acid ethyl ester |
| CN111978205B (en) * | 2020-08-12 | 2023-04-28 | 上海应用技术大学 | Method and device for continuously synthesizing 4-chloro-2-methoxyiminoacetoacetic acid ethyl ester |
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