CN1709879A - Method for preparing (2)-2-(2-amino-4-thiazole)-2-hydroxy imine acetate and its derivative - Google Patents

Method for preparing (2)-2-(2-amino-4-thiazole)-2-hydroxy imine acetate and its derivative Download PDF

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CN1709879A
CN1709879A CN 200510049999 CN200510049999A CN1709879A CN 1709879 A CN1709879 A CN 1709879A CN 200510049999 CN200510049999 CN 200510049999 CN 200510049999 A CN200510049999 A CN 200510049999A CN 1709879 A CN1709879 A CN 1709879A
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thiazole
amino
derivative
acetic ester
hydroxyl imide
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CN1313452C (en
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任红阳
厉昆
陈亮
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APELOA PHARMACEUTICAL Co.,Ltd.
ZHEJIANG APELOA TOSPO PHARMACEUTICAL Co.,Ltd.
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ZHEJIANG PULUO CHEMISTRY CO Ltd
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Abstract

This invention involves a synthetic method to (Z)-2-(2-amido-4-thiazole)-2-hydroxyamine acetate and its derivatives, especially involves chlorine and (Z)-2-hydroxylamine-acetoacetic acid ester and its derivatives react to (Z)-4-chlorin-2-hydroxylamine-acetoacetic acid ester and its derivatives (I).Adopt reaction of three steps to prepare (Z)-2-(2-amido-4-thiazole)-2-hydroxyamine acetate (II), use chlorine substitute bromine as halogenation agents, reduced cost of production in evidence. Thereinto, R is H, -CH2CH3, -CH3, -CH2COOCH3, -C(CH2)2COOC (CH3) 3,-CH2Ph2, etc.

Description

The method of preparation (Z)-2-(2-amino-4-thiazole)-2-hydroxyl imide acetic ester and derivative thereof
Technical field
The invention relates to preparation (Z)-2-(2-amino-4-thiazole)-2-hydroxyl imide acetic ester and derivative thereof, particularly replace bromine to finish the method for halogenating reaction with chlorine.
Technical background
When the side chain of the functional 7-of parent nucleus position such as synthetic cefotaxime acid, cephalo demethyl ainothiazoly loximate, Wincef, Cefixime Micronized, Cefdinir, ceftazime, ceftriaxone, all need make intermediate with (Z)-2-(2-amino-4-thiazole)-2-hydroxyl imide acetic ester or derivatives thereof.
About synthesizing of (Z)-2-(2-amino-4-thiazole)-2-hydroxyl imide acetic ester and derivative thereof, existing more foreign patent is reported (as US4202893; US4458072; DE 2812625; JP63126870), synthetic route is divided by starting raw material roughly two classes: acetylacetic ester route and 4-chloro acetylacetic ester route.For example,
Above-mentioned reaction scheme (2) adopts SO 2Cl 2Make halogenating agent, the reaction times is long, and SO 2Cl 2Consumption is required to be by more than 2 times of halides mole number, and the waste gas of generation is many, substantially need not in the production.Reaction scheme (3) is made raw material with the 4-chloro ethyl acetoacetate, and cost an arm and a leg (generally exceeding methyl aceto acetate more than 4 times) causes industrial cost to be difficult to bear.Because the activity of bromine is lower, reaction relatively relaxes, and the inside and outside factory in native land generally adopts reaction scheme (1) (it is relevant with product category whether oximido carries out alkylation reaction).The shortcoming of reaction scheme (1) is that related bromine molecular weight is bigger, and the unit price costliness is so production cost is higher.Directly carry out halogenating reaction if adopt chlorine to substitute bromine, then chlorination speed is slower generally speaking, and many chloros by product is wayward, (Z)-and the yield of 4-chloro-2-hydroxyl imide-acetylacetic ester and derivative thereof is lower; In addition, (Z)-4-chloro-2-hydroxyl imide-acetylacetic ester and derivative thereof and thiocarbamide speed of response are slower, (Z)-yield of 2-(2-amino-4-thiazole)-2-hydroxyl imide acetic ester or derivatives thereof is lower when reacting than with bromine.
The invention technology
The objective of the invention is to overcome the deficiency on the above-mentioned prior art, (Z)-2-(2-amino-4-the thiazole)-2-hydroxyl imide acetic ester that a kind of production cost has bigger reduction and the synthetic method of derivative thereof are provided.
The synthetic method of (Z)-2-provided by the invention (2-amino-4-thiazole)-2-hydroxyl imide acetic ester and derivative thereof, select suitable solvent, catalyzer and temperature of reaction to make chlorination reaction become gentle, select for use suitable phase-transfer catalyst to make (Z)-4-chloro-2-hydroxyl imide-acetylacetic ester and derivative and thiocarbamide speed of response thereof accelerate simultaneously, yield improves.
Adopt three-step reaction preparation (Z)--2-(2-amino-4-thiazole)-2-hydroxyl imide acetic ester, step is as follows:
Figure A20051004999900052
For (Z)--the derivative of 2-(2-amino-4-thiazole)-2-hydroxyl imide acetic ester,
Change and before chlorination, to carry out corresponding alkylation reaction according to product category oximido;
Described R 1=H;-CH 2CH 3-CH 3-CH 2COOCH 3-C (CH 3) 2COOC (CH 3) 3-CH 2Ph 2Deng:
Described R 2=-CH 3-CH 2CH 3-C (CH 3) 3-CH 2Ph 2Deng;
In step (B), suitable solvent is protonic solvent or polar aprotic solvent;
In step (B), appropriate catalyst is organic bases solvent or organic amine inorganic acid salt;
In step (B), suitable reaction temperature is-70～80 ℃ of scopes, and preferred temperature is-20～40 ℃;
In step (C), suitable phase-transfer catalyst is quaternary ammonium salt or polyoxyethylene glycol.
In step (B), suitable solvent is protonic solvent and polar aprotic solvent, and protonic solvent is one or more mixing of methyl alcohol, ethanol, propyl alcohol, butanols etc.Polar aprotic solvent comprises amides, sulfoxide class, nitrile and ethers, amides is N, dinethylformamide, N, one or both mixing of N-N,N-DIMETHYLACETAMIDE etc., sulfoxide class such as dimethyl sulfoxide (DMSO) etc., nitrile such as acetonitrile etc., ethers are one or more mixing of tetrahydrofuran (THF), dioxane, diethylene glycol monoethyl ether, the two ether of glycol ether etc.
In step (B), appropriate catalyst is organic amine and nitrogen-containing heterocycle compound and inorganic acid salt, acid amides, N-halogen acid amide, hydrazine class and inorganic acid salt, hydrazides or urea.
In step (B), appropriate catalyst is an organic amine, and organic amine comprises tertiary amine, secondary amine, primary amine.Organic amine is R 1R 2R 3N, wherein R 1, R 2, R 3Be hydrogen, C 1-C 18Alkyl, alkylidene group or alkylene, R 1, R 2, R 3Also can be C 5-C 8Cycloalkyl or cycloalkenyl group, R 1, R 2, R 3Can also be aryl.R 1, R 2, R 3Can be identical group, also can be different groups.For example, tertiary amines such as triethylamine, tri-n-butylamine, trioctylamine, N, N-dimethyl amino dodecane, N, N-dimethyl cetylamine, N, Dymanthine, N, N-dimethylcyclohexylamine, crow are as if tropine, triethylene diamine, N, accelerine etc.Secondary amine class such as dimethylamine, diethylamine, dipropyl amine, Di-n-Butyl Amine, distearyl amine, diethylenetriamine, ethylenimine, cyclopropylamine, U-4527, ring imines in heptan, dicyclohexyl amine etc.Primary amine class such as Monomethylamine, monoethylamine, a propylamine, Isopropylamine, n-Butyl Amine 99, isobutylamine, sec-butylamine, TERTIARY BUTYL AMINE, hexylamine, decyl amine, amino dodecane, cetylamine, stearylamine, quadrol, 1,2-propylene diamine, 1,4-butanediamine, 1,6-hexanediamine, 1, tetrahydrobenzene ethamine, aniline etc.
In step (B), appropriate catalyst is a nitrogen-containing heterocycle compound, and nitrogen-containing heterocycle compound is one or more mixing of pyrroles, imidazoles, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline 99.9, indoles etc.
In step (B), appropriate catalyst is the inorganic acid salt of above-mentioned tertiary amine, secondary amine, primary amine and nitrogen-containing heterocycle compound, and inorganic acid radical is chlorion, bromide anion, bisulfate ion, sulfate radical, dihydrogen phosphate, hydrogen phosphate, phosphate radical, nitrate radical.
In step (B), appropriate catalyst is amides R 1CONR 2R 3, R wherein 1Be C 1-C 18Alkyl, alkylidene group or unsaturated alkyl, R 1Also can be C 5-C 8Cycloalkyl or cycloalkenyl group, R 1Can also be aryl; R 2And R 3Can be hydrogen, C 1-C 6Alkyl or alkylidene group.R 2, R 3Can be identical group, also can be different groups.For example; amides such as methane amide, ethanamide, propionic acid amide, butyramide, isobutyramide, lauramide, stearylamide, N-methylformamide, N-methylacetamide, N-stearyl-quadrol, N; dinethylformamide, N; N-N,N-DIMETHYLACETAMIDE, N; N-dibutyl acetamide, N; N-diethylcapramide, methylene-bis stearylamide, the two stearylamides of mute ethyl, N, N '-dimethyl oxalamide, succimide, phthalic imidine, hexanolactam, oenantholactam, laurolactam, N-methyl caprolactam, pyrrolidone etc.
In step (B), appropriate catalyst is the N-halogen acid amide, the N-halogen acid amide is one or more mixing of N-halo methane amide, N-Haloacetamide, N-halogenated succinimide imide, N-halophthalimide, three halo isocyanuric acids etc., and wherein halogen is a chlorine or bromine.
In step (B), appropriate catalyst is hydrazine class and inorganic acid salt thereof, wherein the hydrazine class is hydrazine, monomethylhydrazine, 1, one or more mixing of 1-dimethylhydrazine etc., inorganic acid radical is chlorion, bromide anion, bisulfate ion, sulfate radical, dihydrogen phosphate, hydrogen phosphate, phosphate radical, nitrate radical.
In step (B), appropriate catalyst is a hydrazides, and hydrazides is formyl hydrazine, daminozide, N, one or more mixing of N '-diformylhydrazine, N-methyl dimethoxy hydrazides etc.
In step (B), appropriate catalyst is a urea, urea be ethyl carbamide, tert butyl urea, ethylidene-urea, methoxyl group isourea, Urea,amino-, N, one or more mixing of N '-Dimethylurea, tetramethyl-urea etc.
In step (B), suitable reaction temperature is a low temperature, and scope is-70～80 ℃, and preferred temperature is-20～40 ℃.
In step (C), suitable phase-transfer catalyst is a quaternary ammonium salt, and quaternary ammonium salt is one or more mixing of tetramethyl ammonium chloride, 4 bromide, Tetrabutyl amonium bromide, tetrabutylammonium chloride, benzyltriethylammoinium chloride (TEBA), tetraethylammonium bromide etc.; Suitable phase-transfer catalyst also can be polyglycol ether etc.
In step (C), the ring-closure reaction temperature is 20～40 ℃.
The present invention makes chlorination become gentle by selecting suitable solvent, catalyzer and temperature of reaction, and the content of gained 4-chloro-2-hydroxyl imide-acetylacetic ester and derivative thereof is more than 85%, and the dichloro-thing is below 8%.Select for use suitable phase-transfer catalyst that (Z)-4-chloro-2-hydroxyl imide-acetylacetic ester and derivative and thiocarbamide speed of response thereof are accelerated simultaneously, yield improves, thereby reaches the purpose that obviously reduces production costs.
Below in conjunction with indefiniteness embodiment, further specify the inventive method.
Embodiment 1
(A) (Z)-preparation of 2-hydroxyl imide-tert-butyl acetoacetate
Three-necked bottle has stirring, thermometer and minim pipette, the outer wall cryosel.In three-necked bottle, add 31.6g tert-butyl acetoacetate (0.2mol), 16.6 Sodium Nitrites (0.24mol) and 200ml water, be cooled to-15～-12 ℃ and slowly drip 15.0g glacial acetic acid (0.25mol) down, drip off in 2 hours.The chromatographic sheet point sample is analyzed, question response fully the back with twice of 2 * 100ml ethyl acetate extraction.Ethyl acetate layer is with 2 * 100ml saturated nacl aqueous solution washed twice, oil reservoir Calcium Chloride Powder Anhydrous drying.Filter, the reclaim under reduced pressure ethyl acetate solvent gets 36.5g (Z)-2-hydroxyl imide-tert-butyl acetoacetate (efficient liquid phase chromatographic analysis content 97%, 0.189mol, yield are 95.5%)
(B) (Z)-preparation of 4-chloro-2-hydroxyl imide-etheric acid
With 28.9g 2-hydroxyl imide-tert-butyl acetoacetate (content 97%, 0.15mol), 100ml methyl alcohol mixes with the 3ml triethylamine, feeds 28.8g Cl in 0 ℃, 3 hours 2(0.4mol), back insulation 2 hours finishes, slowly add 50ml water, standing demix, the oil reservoir anhydrous magnesium sulfate drying filters, filtrate is cooled to-20 ℃ of crystallizatioies, obtain off-white color crystal 2 4g 4-chloro-2-hydroxyl imide-etheric acid (efficient liquid phase chromatographic analysis content 92.2%, 0.12mol, yield 80%).
(C) (Z)-preparation of 2-(2-amino-4-thiazole)-2-hydroxyl imide acetate
7g thiocarbamide (0.09mol), 100ml methyl alcohol and 100ml water are mixed, add 1g polyglycol ether 400 again, drip 12g (Z)-2-(2-amino-4-thiazole)-2-hydroxyl imide acetate (content 92.2% in 20～25 ℃ of following 1h of temperature, 0.06mol,), stirred 3 hours, separate out white solid.Get 8g (Z)-2-(2-amino-4-thiazole)-2-hydroxyl imide acetate (efficient liquid phase chromatographic analysis content 99.3%, 0.043mol, yield 71.6%).
Embodiment 2
(A) (Z)-preparation of 2-hydroxyl imide-methyl aceto acetate
Add 130g methyl aceto acetate (1.0mol), 82.8g Sodium Nitrite (1.2mol) and 1000g water, temperature drops to 2 ℃, slowly drips 184ml 29% sulfuric acid (0.625mol), dropwises afterwards in 8 ℃ of insulation reaction 3 hours.Leave standstill branch and get organic layer.The water layer ethyl acetate extraction merges organic layer and acetic acid ethyl ester extract, uses the Calcium Chloride Powder Anhydrous drying.Filter, decompression and solvent recovery gets 150g 2-hydroxyl imide-methyl aceto acetate (efficient liquid phase chromatographic analysis content 98%, 0.92mol, yield 92%)
(B) preparation of 4-chloro-2-hydroxyl imide-methyl aceto acetate
(content 98% 0.1mol) is dissolved in the 200ml ethanol, adds the 2ml methane amide, and in 15 ℃, slowly logical chlorine was taken a sample after 5 hours, and efficient liquid phase chromatographic analysis finds that raw material is less than 5%, as reaction end with 16.3g 2-hydroxyl imide-methyl aceto acetate.Deoil a layer decompression and solvent recovery, drying, oily 20g 4-chloro-2-hydroxyl imide-methyl aceto acetate (efficient liquid phase chromatographic analysis one chloro thing content 86%, 0.088mol, yield 88%).
(C) (Z)-preparation of 2-(2-amino-4-thiazole)-2-hydroxyl imide ethyl acetate
7.6g thiocarbamide (0.1mol), 100ml methyl alcohol and 100ml water are mixed, add the 1g Tetrabutyl amonium bromide again, temperature is controlled at below 20 ℃, slowly drips above-mentioned oily matter 20g 4-chloro-2-hydroxyl imide-methyl aceto acetate (content 86%, 0.088mol), dropwise,, be cooled to 15 ℃ in 35 ℃ of insulations 2 hours, suction filtration obtains faint yellow solid 18g (185～190 ℃ of fusing points, efficient liquid phase chromatographic analysis content 98.5%, 0.083mol, yield 94.3%).
Embodiment 3
(A) (Z)-preparation of 2 methoxy iminos-methyl aceto acetate
With 16.2g 2-hydroxyl imide-ethyl 3-oxobutanoate (content 98%, 0.10mol) be dissolved in 150mL water and the 50mL methyl alcohol, in-5 ℃, 1h, drip 12.6g methyl-sulfate (0.1mol), be cooled to-10 ℃ then and add 21.2g yellow soda ash (0.2mol), insulation reaction 10 hours is warmed up to room temperature, adds water 100mL, layering is with twice of 2 * 50mL ethyl acetate extraction water layer.Merge organic layer and acetic acid ethyl ester extract, use anhydrous magnesium sulfate drying, filter, filtrate decompression is reclaimed solvent, get 16.9g 2-methoxy imino-methyl aceto acetate (efficient liquid phase chromatographic analysis content 97%, 0.095mol, yield 95%).
(B) preparation of 4-chloro-2-methoxy imino-methyl aceto acetate
(content 97% 0.112mol) is dissolved in methyl alcohol 200ml, adds the 2ml pyridine again, slowly leads to chlorine 5 hours in 0 ℃, and efficient liquid phase chromatographic analysis is used in sampling, and raw material is decided to be reaction end less than 5% with 20g 2-methoxy imino-methyl aceto acetate.Slowly add 50ml water, standing demix is with twice of 2 * 50mL ethyl acetate extraction water layer.Merge organic layer and acetic acid ethyl ester extract, the anhydrous anhydrous magnesium sulfate drying of oil reservoir filters, decompression and solvent recovery, get 23g oily 4-chloro-2-methoxy imino-methyl aceto acetate (efficient liquid phase chromatographic analysis one chloro thing content 90%, 0.099mol, yield 88.3%).
(C) (Z)-preparation of 2-(2-amino-4-thiazole)-2-methoxy imino-ethyl acetate
7.6g thiocarbamide (0.1mol), 100ml methyl alcohol and 100ml water are mixed, add the 1g tetrabutylammonium chloride again, temperature is controlled at below 20 ℃, slowly drip 23g (Z)-4-chloro-2-methoxy imino-methyl aceto acetate (content 90%, 0.099mol), dropwise the back in 35 ℃ of insulations 2 hours, be cooled to 15 ℃, suction filtration obtains faint yellow solid 18g (fusing point＞180 ℃, efficient liquid phase chromatographic analysis content 99%, 0.077mol, yield 77.8%).
Embodiment 4-7
Change the chlorination catalyst type, catalyst levels be by the 3-5% of chloro feed molar number, other working method fully with embodiment 1 with, each goes on foot reacts molar yield and is listed as follows.
The chlorination catalyzer (A) yield % (B) yield % (C) yield %
Quadrol ??95 ??78 ??71
Pyridine ??95 ??80 ??69
Three chloro isocyanuric acids ??95 ??75 ??70
N, N '-Dimethylurea ??95 ??90 ??73

Claims (10)

  1. , the synthetic method of a kind of (Z)-2-(2-amino-4-thiazole)-2-hydroxyl imide acetic ester and derivative thereof, adopt three-step reaction preparation (Z)--2-(2-amino-4-thiazole)-2-hydroxyl imide acetic ester, step is as follows:
    Figure A2005100499990002C3
    Described R 1=H;-CH 2CH 3-CH 3-CH 2COOCH 3-C (CH 3) 2COOC (CH 3) 3-CH 2Ph 2
    In step (B), suitable solvent is protonic solvent or polar aprotic solvent;
    In step (B), appropriate catalyst is organic amine and nitrogen-containing heterocycle compound and inorganic acid salt, acid amides, N-halogen acid amide, hydrazine class and inorganic acid salt, hydrazides or urea;
    In step (B), suitable reaction temperature is-70～80 ℃ of scopes, and preferred temperature is-20～40 ℃;
    In step (C), suitable phase-transfer catalyst is quaternary ammonium salt or polyoxyethylene glycol.
  2. 2, according to the synthetic method of claim 1 (Z)-2-(2-amino-4-thiazole)-2-hydroxyl imide acetic ester and derivative thereof, it is characterized in that for (Z)--the derivative of 2-(2-amino-4-thiazole)-2-hydroxyl imide acetic ester,
    Change and before chlorination, to carry out corresponding alkylation reaction, R according to product category oximido 2=-CH 3-CH 2CH 3-C (CH 3) 3-CH 2Ph 2
  3. 3, according to the synthetic method of described (the Z)-2-of claim 1 (2-amino-4-thiazole)-2-hydroxyl imide acetic ester and derivative thereof, it is characterized in that described protonic solvent be in methyl alcohol, ethanol, propyl alcohol, the butanols-kind or several mixing.
  4. 4, according to the synthetic method of described (the Z)-2-of claim 1 (2-amino-4-thiazole)-2-hydroxyl imide acetic ester and derivative thereof, it is characterized in that described polar aprotic solvent acid amides, sulfoxide, nitrile or ether, amide solvent is N, one or both mixing of dinethylformamide, N,N-dimethylacetamide; The sulfoxide kind solvent is a dimethyl sulfoxide (DMSO); Nitrile solvents is an acetonitrile, and ether solvent is one or more mixing of tetrahydrofuran (THF), dioxane, diethylene glycol monoethyl ether, the two ether of glycol ether.
  5. 5,, it is characterized in that described chlorination reaction catalyzer is organic amine R according to the synthetic method of described (the Z)-2-of claim 1 (2-amino-4-thiazole)-2-hydroxyl imide acetic ester and derivative thereof 1R 2R 3N, wherein R 1, R 2, R 3Be C 1-C 18Hydrogen, alkyl, alkylidene group or alkylene, R 1, R 2, R 3Also can be C 5-C 8Cycloalkyl or cycloalkenyl group, R 1, R 2, R 3Can also be aryl.R 1, R 2, R 3Can be identical group, also can be different groups.
  6. 6, according to the synthetic method of described (the Z)-2-of claim 1 (2-amino-4-thiazole)-2-hydroxyl imide acetic ester and derivative thereof, it is characterized in that described chlorination reaction catalyzer is a nitrogen-containing heterocycle compound, nitrogen-containing heterocycle compound is one or more mixing of pyrroles, imidazoles, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline 99.9, indoles.
  7. 7, according to the synthetic method of described (the Z)-2-of claim 1 (2-amino-4-thiazole)-2-hydroxyl imide acetic ester and derivative thereof, it is characterized in that described chlorination reaction catalyzer is the inorganic acid salt of claim 5,6 described organic amines and nitrogen-containing heterocycle compound, inorganic acid radical is chlorion, bromide anion, bisulfate ion, sulfate radical, dihydrogen phosphate, hydrogen phosphate, phosphate radical, nitrate radical.
  8. 8,, it is characterized in that described chlorination reaction catalyzer is acid amides R according to the synthetic method of described (the Z)-2-of claim 1 (2-amino-4-thiazole)-2-hydroxyl imide acetic ester and derivative thereof 1CONR 2R 3, R wherein 1Be C 1-C 18Alkyl, alkylidene group or unsaturated alkyl, R 1Also can be C 5-C 8Cycloalkyl or cycloalkenyl group, R 1Can also be aryl; R 2And R 3Can be hydrogen, C 1-C 6Alkyl or alkylidene group.R 2, R 3Can be identical group, also can be different groups.
  9. 9, according to the synthetic method of described (the Z)-2-of claim 1 (2-amino-4-thiazole)-2-hydroxyl imide acetic ester and derivative thereof, it is characterized in that described chlorination reaction catalyzer is the N-halogen acid amide, the N-halogen acid amide is one or more mixing of N-halo methane amide, N-Haloacetamide, N-halogenated succinimide imide, N-halophthalimide, three halo isocyanuric acids etc., and wherein halogen is a chlorine or bromine.
  10. 10, according to the synthetic method of described (the Z)-2-of claim 1 (2-amino-4-thiazole)-2-hydroxyl imide acetic ester and derivative thereof, it is characterized in that described phase-transfer catalyst quaternary ammonium salt is: one or more of tetramethyl ammonium chloride, 4 bromide, Tetrabutyl amonium bromide, tetrabutylammonium chloride, benzyltriethylammoinium chloride (TEBA), tetraethylammonium bromide.
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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
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CN114853691A (en) * 2021-12-27 2022-08-05 浙江普洛得邦制药有限公司 Method for continuously preparing (Z) -2- (2-amino-4 thiazole) acetic acid by using microchannel reactor

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CN106699681B (en) * 2016-12-30 2020-03-20 淄博鑫泉医药技术服务有限公司 Synthetic method of ethyl noraminothiazolyloximate
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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
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