CN103012313A - Synthetic method of aminothiazoly loximate - Google Patents
Synthetic method of aminothiazoly loximate Download PDFInfo
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- CN103012313A CN103012313A CN2012105144541A CN201210514454A CN103012313A CN 103012313 A CN103012313 A CN 103012313A CN 2012105144541 A CN2012105144541 A CN 2012105144541A CN 201210514454 A CN201210514454 A CN 201210514454A CN 103012313 A CN103012313 A CN 103012313A
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- ainothiazoly loximate
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- loximate
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- 238000002360 preparation method Methods 0.000 claims abstract description 19
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 14
- -1 nitrous acid ester Chemical class 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 230000007062 hydrolysis Effects 0.000 claims abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 6
- 238000007670 refining Methods 0.000 claims abstract description 6
- 230000000694 effects Effects 0.000 claims abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 239000012043 crude product Substances 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 229960000583 acetic acid Drugs 0.000 claims description 8
- 239000003444 phase transfer catalyst Substances 0.000 claims description 8
- 239000012362 glacial acetic acid Substances 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 5
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- 239000001632 sodium acetate Substances 0.000 claims description 5
- 229960004249 sodium acetate Drugs 0.000 claims description 5
- 235000017281 sodium acetate Nutrition 0.000 claims description 5
- 235000017550 sodium carbonate Nutrition 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 4
- QQZWEECEMNQSTG-UHFFFAOYSA-N Ethyl nitrite Chemical compound CCON=O QQZWEECEMNQSTG-UHFFFAOYSA-N 0.000 claims description 3
- BLLFVUPNHCTMSV-UHFFFAOYSA-N methyl nitrite Chemical compound CON=O BLLFVUPNHCTMSV-UHFFFAOYSA-N 0.000 claims description 3
- KAOQVXHBVNKNHA-UHFFFAOYSA-N propyl nitrite Chemical compound CCCON=O KAOQVXHBVNKNHA-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 235000010755 mineral Nutrition 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 12
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 229930186147 Cephalosporin Natural products 0.000 abstract description 4
- 229940124587 cephalosporin Drugs 0.000 abstract description 4
- 150000001780 cephalosporins Chemical class 0.000 abstract description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 abstract description 4
- 230000001988 toxicity Effects 0.000 abstract description 4
- 231100000419 toxicity Toxicity 0.000 abstract description 4
- 238000007034 nitrosation reaction Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 abstract description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 abstract description 2
- 229910017053 inorganic salt Inorganic materials 0.000 abstract description 2
- 238000006146 oximation reaction Methods 0.000 abstract description 2
- 235000010288 sodium nitrite Nutrition 0.000 abstract description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 abstract 2
- 230000009935 nitrosation Effects 0.000 abstract 2
- 230000002152 alkylating effect Effects 0.000 abstract 1
- 239000012320 chlorinating reagent Substances 0.000 abstract 1
- YXJZAMRXWYECTM-UHFFFAOYSA-N ethyl 2-methoxyiminoacetate Chemical compound CCOC(=O)C=NOC YXJZAMRXWYECTM-UHFFFAOYSA-N 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 239000002253 acid Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000009413 insulation Methods 0.000 description 3
- 239000012264 purified product Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000003814 drug Substances 0.000 description 2
- 229940093858 ethyl acetoacetate Drugs 0.000 description 2
- XSPUSVIQHBDITA-KXDGEKGBSA-N (6r,7r)-7-[[(2e)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(5-methyltetrazol-2-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)/C(=N/OC)C=2N=C(N)SC=2)CC=1CN1N=NC(C)=N1 XSPUSVIQHBDITA-KXDGEKGBSA-N 0.000 description 1
- MMRINLZOZVAPDZ-LSGRDSQZSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(1-methylpyrrolidin-1-ium-1-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;chloride Chemical compound Cl.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 MMRINLZOZVAPDZ-LSGRDSQZSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960002100 cefepime Drugs 0.000 description 1
- 229960002129 cefixime Drugs 0.000 description 1
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 description 1
- 229960001958 cefodizime Drugs 0.000 description 1
- XDZKBRJLTGRPSS-BGZQYGJUSA-N cefodizime Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(C)=C(CC(O)=O)S1 XDZKBRJLTGRPSS-BGZQYGJUSA-N 0.000 description 1
- 229960004261 cefotaxime Drugs 0.000 description 1
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 description 1
- DKOQGJHPHLTOJR-WHRDSVKCSA-N cefpirome Chemical compound N([C@@H]1C(N2C(=C(C[N+]=3C=4CCCC=4C=CC=3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 DKOQGJHPHLTOJR-WHRDSVKCSA-N 0.000 description 1
- 229960000466 cefpirome Drugs 0.000 description 1
- 229960005090 cefpodoxime Drugs 0.000 description 1
- WYUSVOMTXWRGEK-HBWVYFAYSA-N cefpodoxime Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)C(=O)C(=N/OC)\C1=CSC(N)=N1 WYUSVOMTXWRGEK-HBWVYFAYSA-N 0.000 description 1
- 229950000679 cefteram Drugs 0.000 description 1
- WJXAHFZIHLTPFR-JLRJEBFFSA-N ceftiolene Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1\C=C\SC1=NNC(=O)C(=O)N1CC=O WJXAHFZIHLTPFR-JLRJEBFFSA-N 0.000 description 1
- 229950008880 ceftiolene Drugs 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Landscapes
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The invention relates to a synthetic method of aminothiazoly loximate, which belongs to the synthetic method of a heterocyclic compound containing 1,3-thiazole ring, and in particular relates to a preparation method of the heterocyclic compound with two double bonds between the annular atoms and without other condensed rings. The method comprises the steps of: (1) using ethyl acetoacetate as a raw material, oximating, alkylating and cyclizing in a same reaction container to obtain ethyl methoxyiminoacetate; (2) modifying a nitrosation reagent in an oximation agent into organic nitrous acid ester by inorganic salt sodium nitrite, wherein organic nitrous acid ester is more suitable for the solvent system and the nitrosation effect is better; (3) hydrolysis: preparing an aminothiazoly loximate coarse product; and (4) refining: preparing an aminothiazoly loximate product. According to the process, the operating process of the reaction is simplified, the production cost is lowered, and the emission of three wastes is reduced. A triphosgene chlorinating agent which is smaller in toxicity, safe and convenient to use, easy to control and operate and high in yield is provided. Aminothiazoly loximate is a raw material for synthesizing third generation cephalosporin, and is an important medical intermediate.
Description
Technical field
The present invention is a kind of synthetic method of ainothiazoly loximate, belongs to the heterogeneous ring compound synthetic method that contains 1,3 thiazole ring, does not particularly contain the preparation method that the heterogeneous ring compound of two two keys is arranged between the annular atoms of other condensed ring.
Background technology
The ainothiazoly loximate chemical name is 2-methoxy imino-2-(thiazolamine)-4-acetic acid, English 2-(2-Aminothiazole-4-yl) by name-2-methoxyiminoacetic acid, and structural formula is:
Ainothiazoly loximate is a kind of important medicine intermediate, is the raw material for the synthesis of third generation cephalosporin.The ainothiazoly loximate cephalosporins is for having good curative effect by the infection due to some resistant organisms and the pathogenic bacteria rambunctious, and toxicity is low, broad-spectrum long-acting, and its curative effect is than the high decades of times of penicillin.Utilize the ainothiazoly loximate compounds to mainly contain as the synthetic cephalosporins medicine of antibiotic side chain: Cefixime Micronized, Cefpodoxime, cefotaxime, cefepime, cefteram, Cefodizime, cefpirome, ceftiolene etc.
Traditional method for preparing ainothiazoly loximate mainly contains: methyl acetoacetate method, ethyl acetoac etate process, 4-ethyl acetoac etate process.
In the above-mentioned prior art, the synthetic method of ainothiazoly loximate remains in following technical problem:
(1) production cycle long, the intermediate product in the production process be difficult for to detect, and uses the many production costs of production unit high, it is many to produce the waste water that produces, the three wastes are many.
(2) the nitrosation reaction technological process is inhomogeneous reaction, and it is long that not only speed of response causes the cycle slowly, and yield is low.
(3) in the chloridization process process take chlorine as chlorizating agent, react wayward, and its toxicity is large, has potential safety hazard.
Summary of the invention
The object of the present invention is to provide a kind of synthetic method of ainothiazoly loximate, shorten reaction time, improve speed of reaction.
The synthetic method of ainothiazoly loximate of the present invention, carry out according to the following steps:
(1) preparation Ethyl Methylaminothiazolyloximate
The oximate agent adopts nitrous acid ester to add Glacial acetic acid, and the ratio of its weight fraction is nitrous acid ester: Glacial acetic acid is 1:1 ~ 5, and the consumption of oximate agent is 1 ~ 3 times of methyl aceto acetate, and under 0 ~ 5 ℃, methyl aceto acetate and oximate agent were reacted in solvent 1 ~ 4 hour, passed into N
2Removed remaining oximate agent in 1 hour; Then add phase-transfer catalyst in solvent, add hydrocarbonylation reagent of sulfuric acid dimethyl ester and react, the control temperature of reaction system is 5 ~ 15 ℃, and the pH value is 8 ~ 10, and the reaction times is 2 ~ 4 hours, and the consumption of methyl-sulfate is 1 ~ 1.5 times of methyl aceto acetate; A certain amount of organic bases of adding after reaction is finished, add again triphosgene solution, 10 ~ 20 ℃ of control temperature of reaction, 1 ~ 3 hour reaction times, wherein the weight fraction of triphosgene is 0.4 ~ 1.0 times of methyl aceto acetate, and the weight fraction of organic bases is 1% ~ 5% of triphosgene; Add a certain amount of thiocarbamide and sodium-acetate, its consumption is 0.3 ~ 0.7 times and 0.5 ~ 1.2 times of methyl aceto acetate consumption, under the effect of phase-transfer catalyst, the control temperature of reaction is 20 ~ 40 ℃, reacts 3 ~ 5 hours, regulates the pH value, the cooling crystallization gets Ethyl Methylaminothiazolyloximate;
(2) hydrolysis: preparation ainothiazoly loximate crude product
The Ethyl Methylaminothiazolyloximate of preparation in the step (1) is dissolved in a certain amount of sodium hydroxide solution, the concentration of sodium hydroxide solution is sodium hydroxide: water=1:3 ~ 8, the consumption of sodium hydroxide solution is 2 ~ 8 times of Ethyl Methylaminothiazolyloximate, the control temperature is at 20 ~ 50 ℃, and stirring reaction 2 ~ 5 hours is after reaction is finished, use activated carbon decolorizing, regulate the pH value, the cooling crystallization gets the ainothiazoly loximate crude product;
(3) refining: the preparation ainothiazoly loximate
The ainothiazoly loximate crude product refluxed in appropriate solvent 1 ~ 8 hour, cooling crystallization, the ainothiazoly loximate product that obtains making with extra care.
Wherein:
Nitrosification agent changes organic nitrous acid ester into by the Sodium Nitrite inorganic salt in the middle oximate agent of step (1), and organically nitrous acid ester is more suitable for this solvent system, and nitrosification is effective.
Nitrous acid ester described in the step (1) is a kind of in methyl nitrite, ethyl nitrite or the n-propyl nitrite.
Solvent described in the step (1) is ethanolic soln, and its consumption is 2 ~ 5 times of methyl aceto acetate.
Phase-transfer catalyst described in the step (1) is a kind of in tetrabutylammonium iodide, cetyl trimethylammonium bromide or the benzyl triethyl ammonium bromide, and the consumption of phase-transfer catalyst is 0.5 ~ 10% of methyl aceto acetate volume.
Organic bases described in the step (1) is triethylamine or DMF.
The used mineral alkali of adjusting pH value described in the step (1) is a kind of in yellow soda ash, salt of wormwood or the sodium hydroxide.
The scope of the pH value described in the step (2) is 2 ~ 3.
Tell solvent in the step (3) and be a kind of in methyl alcohol, ethanol, methylene dichloride or the chloroform.
The present invention has the following advantages:
1. adopt the method for one kettle way, oximate, hydrocarbonylation, chlorination, the cyclization of finishing methyl aceto acetate in a reaction vessel prepare Ethyl Methylaminothiazolyloximate, have simplified operating process, have reduced production cost, have reduced the discharging of the three wastes.
2. a kind of oximate agent system that is suitable for the homogeneous phase oximation reaction is provided, to improve speed of reaction, has shortened the production cycle.
3. the chlorizating agent toxicity that provides is little, operational safety, convenience, be easy to control.
4. the yield of ainothiazoly loximate product 〉=79.1%.
5. the purity of ainothiazoly loximate product 〉=99.20%, fusing point: 181.0 ~ 183.6 ℃.
Embodiment
The present invention will be further described below in conjunction with embodiment.
Embodiment 1
(1) add aqueous ethanolic solution (volume ratio 1:2) 60mL, methyl aceto acetate 20mL, ethyl nitrite 11g in there-necked flask, stir, 5 ± 3 ℃ of temperature drip the 25g Glacial acetic acid, and 1h adds, and adds rear continuation stirring reaction 2h; After finishing, reaction passes into N
2Then 1h adds the 0.4g tetrabutylammonium iodide, begins to drip methyl-sulfate 20mL, 11 ± 3 ℃ of control temperature, and the pH value is 8, reaction 2h; The 10g triphosgene is dissolved in the 20mL chloroform and adds 0.5mLDMF, be made into triphosgene solution, after question response is finished, slowly add the triphosgene solution for preparing, 15 ± 3 ℃ of control temperature of reaction, reaction 2h; Adding aqueous ethanolic solution 10mL after reaction is finished, add 8g thiocarbamide, 16g sodium-acetate and 0.5g tetrabutylammonium iodide, 30 ± 3 ℃ of control temperature of reaction, time for adding is 1.5h, drip off insulation 2h, regulate pH value 7.0 with sodium carbonate solution, be incubated the complete crystallization below 0 ℃ that is cooled to, centrifugal, the dry Ethyl Methylaminothiazolyloximate that gets.
(2) hydrolysis: preparation ainothiazoly loximate crude product
The Ethyl Methylaminothiazolyloximate of preparation in the step 1 is dissolved in the 95mL20% sodium hydroxide solution 27 ± 3 ℃ of control temperature, stirring reaction 3h.React complete after, use activated carbon decolorizing, then use salt acid for adjusting pH value to 2.8, be cooled to crystallization below 0 ℃, centrifugal, dry ainothiazoly loximate crude product.
(3) refining: the preparation ainothiazoly loximate
With ainothiazoly loximate crude product reflux 6h in methyl alcohol, be cooled to crystallize out below 0 ℃, centrifugal, be drying to obtain the ainothiazoly loximate purified product, purity 99.21%, yield 79.2%, 181.4 ~ 183.4 ℃ of fusing points.
Embodiment 2
(1) add aqueous ethanolic solution (volume ratio 1:2) 60mL, methyl aceto acetate 20mL, methyl nitrite 11g in there-necked flask, stir, 3 ± 3 ℃ of temperature drip the 48g Glacial acetic acid, and 1h adds, and adds rear continuation stirring reaction 2h; After finishing, reaction passes into N
2Then 1h adds the 0.6g benzyl triethyl ammonium bromide, begins to drip methyl-sulfate 20mL, 12 ± 3 ℃ of control temperature, and the pH value is 9, reaction 3h; The 10g triphosgene is dissolved in the 20mL chloroform and adds the 0.5mL triethylamine, be made into triphosgene solution, after question response is finished, slowly add the triphosgene solution for preparing, 16 ± 3 ℃ of control temperature of reaction, reaction 2.5h; Adding aqueous ethanolic solution 10mL after reaction is finished, add 8g thiocarbamide, 16g sodium-acetate and 0.7g benzyl triethyl ammonium bromide, 27 ± 3 ℃ of control temperature of reaction, time for adding is 1.5h, drip off insulation 2h, regulate pH value 7.4 with sodium carbonate solution, be incubated the complete crystallization below 0 ℃ that is cooled to, centrifugal, the dry Ethyl Methylaminothiazolyloximate that gets.
(2) hydrolysis: preparation ainothiazoly loximate crude product
The Ethyl Methylaminothiazolyloximate of preparation in the step 1 is dissolved in the 95mL20% sodium hydroxide solution 28 ± 3 ℃ of control temperature, stirring reaction 3h.React complete after, use activated carbon decolorizing, then use salt acid for adjusting pH value to 2.5 ~ 3.0, be cooled to crystallization below 0 ℃, centrifugal, dry ainothiazoly loximate crude product.
(3) refining: the preparation ainothiazoly loximate
With ainothiazoly loximate crude product reflux 6h in ethanol, be cooled to crystallize out below 0 ℃, centrifugal, be drying to obtain the ainothiazoly loximate purified product, purity 99.30%, yield 80.0%, 182.3 ~ 183.6 ℃ of fusing points.
Embodiment 3
(1) add aqueous ethanolic solution (volume ratio 1:2) 60mL, methyl aceto acetate 20mL, n-propyl nitrite 13g in there-necked flask, stir, 5 ± 3 ℃ of temperature drip the 40g Glacial acetic acid, and 1h adds, and adds rear continuation stirring reaction 2h; After finishing, reaction passes into N
2Then 1h adds the 0.8g cetyl trimethylammonium bromide, begins to drip methyl-sulfate 20mL, 9 ± 3 ℃ of control temperature, and the pH value is 8 ~ 10, reaction 4h; The 10g triphosgene is dissolved in the 20mL chloroform and adds 0.5mLDMF, be made into triphosgene solution, after question response is finished, slowly add the triphosgene solution for preparing, 14 ± 3 ℃ of control temperature of reaction, reaction 2.5h; Adding aqueous ethanolic solution 10mL after reaction is finished, add 8g thiocarbamide, 16g sodium-acetate and 0.9g cetyl trimethylammonium bromide, 33 ± 3 ℃ of control temperature of reaction, time for adding is 1.5h, drip off insulation 2h, regulate pH value 7.5 with sodium carbonate solution, be incubated the complete crystallization below 0 ℃ that is cooled to, centrifugal, the dry Ethyl Methylaminothiazolyloximate that gets.
(2) hydrolysis: preparation ainothiazoly loximate crude product
The Ethyl Methylaminothiazolyloximate of preparation in the step 1 is dissolved in the 95mL20% sodium hydroxide solution 29 ± 3 ℃ of control temperature, stirring reaction 3h.React complete after, use activated carbon decolorizing, then use salt acid for adjusting pH value to 3.0, be cooled to crystallization below 0 ℃, centrifugal, dry ainothiazoly loximate crude product.
(3) refining: the preparation ainothiazoly loximate
With ainothiazoly loximate crude product reflux 5h in methyl alcohol, be cooled to crystallize out below 0 ℃, centrifugal, be drying to obtain the ainothiazoly loximate purified product, purity 99.27%, yield 80.6%, 182.4 ~ 183.5 ℃ of fusing points.
Claims (8)
1. the synthetic method of an ainothiazoly loximate is characterized in that: carry out according to the following steps:
(1) preparation Ethyl Methylaminothiazolyloximate
The oximate agent adopts nitrous acid ester to add Glacial acetic acid, and the ratio of its weight fraction is nitrous acid ester: Glacial acetic acid is 1:1 ~ 5, and the consumption of oximate agent is 1 ~ 3 times of methyl aceto acetate, and under 0 ~ 5 ℃, methyl aceto acetate and oximate agent were reacted in solvent 1 ~ 4 hour, passed into N
2Removed remaining oximate agent in 1 hour; Then add phase-transfer catalyst in solvent, add hydrocarbonylation reagent of sulfuric acid dimethyl ester and react, the control temperature of reaction system is 5 ~ 15 ℃, and the pH value is 8 ~ 10, and the reaction times is 2 ~ 4 hours, and the consumption of methyl-sulfate is 1 ~ 1.5 times of methyl aceto acetate; A certain amount of organic bases of adding after reaction is finished, add again triphosgene solution, 10 ~ 20 ℃ of control temperature of reaction, 1 ~ 3 hour reaction times, wherein the weight fraction of triphosgene is 0.4 ~ 1.0 times of methyl aceto acetate, and the weight fraction of organic bases is 1% ~ 5% of triphosgene; Add a certain amount of thiocarbamide and sodium-acetate, its consumption is 0.3 ~ 0.7 times and 0.5 ~ 1.2 times of methyl aceto acetate consumption, under the effect of phase-transfer catalyst, the control temperature of reaction is 20 ~ 40 ℃, reacts 3 ~ 5 hours, regulates the pH value, the cooling crystallization gets Ethyl Methylaminothiazolyloximate;
(2) hydrolysis: preparation ainothiazoly loximate crude product
The Ethyl Methylaminothiazolyloximate of preparation in the step (1) is dissolved in a certain amount of sodium hydroxide solution, the concentration of sodium hydroxide solution is sodium hydroxide: water=1:3 ~ 8, the consumption of sodium hydroxide solution is 2 ~ 8 times of Ethyl Methylaminothiazolyloximate, the control temperature is at 20 ~ 50 ℃, and stirring reaction 2 ~ 5 hours is after reaction is finished, use activated carbon decolorizing, regulate the pH value, the cooling crystallization gets the ainothiazoly loximate crude product;
(3) refining: the preparation ainothiazoly loximate
The ainothiazoly loximate crude product refluxed in appropriate solvent 1 ~ 8 hour, cooling crystallization, the ainothiazoly loximate product that obtains making with extra care.
2. according to claim 1 the synthetic method of ainothiazoly loximate is characterized in that the nitrous acid ester described in the step (1) is a kind of in methyl nitrite, ethyl nitrite or the n-propyl nitrite.
3. according to claim 1 the synthetic method of ainothiazoly loximate is characterized in that the solvent described in the step (1) is ethanolic soln, and its consumption is 2 ~ 5 times of methyl aceto acetate.
4. according to claim 1 the synthetic method of ainothiazoly loximate, it is characterized in that the phase-transfer catalyst described in the step (1) is a kind of in tetrabutylammonium iodide, cetyl trimethylammonium bromide or the benzyl triethyl ammonium bromide, the consumption of phase-transfer catalyst is 0.5 ~ 10% of methyl aceto acetate volume.
5. according to claim 1 the synthetic method of ainothiazoly loximate is characterized in that the organic bases described in the step (1) is triethylamine or DMF.
6. according to claim 1 the synthetic method of ainothiazoly loximate is characterized in that the used mineral alkali of adjusting pH value described in the step (1) is a kind of in yellow soda ash, salt of wormwood or the sodium hydroxide.
7. according to claim 1 the synthetic method of ainothiazoly loximate, the scope that it is characterized in that the pH value described in the step (2) is 2 ~ 3.
8. according to claim 1 the synthetic method of ainothiazoly loximate is characterized in that the solvent described in the step (3) is a kind of in methyl alcohol, ethanol, methylene dichloride or the chloroform.
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Cited By (5)
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| CN106632137A (en) * | 2016-12-29 | 2017-05-10 | 河北合佳医药科技集团股份有限公司 | Method for preparing ethyl 2-(2-aminothiazole-4-yl)-2-methoxyiminoacetate |
| CN107857741A (en) * | 2017-12-15 | 2018-03-30 | 山东金城医药化工有限公司 | The new technique for synthesizing of ainothiazoly loximate |
| CN109796345A (en) * | 2019-01-30 | 2019-05-24 | 青岛科技大学 | A kind of tail gas method of comprehensive utilization of nitrite displacement method production nitromethane |
| CN110372631A (en) * | 2019-07-24 | 2019-10-25 | 东南大学成贤学院 | A kind of preparation method of cefotaxime amide acetaldehyde |
| CN112457211A (en) * | 2020-11-05 | 2021-03-09 | 丽珠集团新北江制药股份有限公司 | Method for preparing ethyl aminothiazolyloximate intermediate |
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| CN106632137A (en) * | 2016-12-29 | 2017-05-10 | 河北合佳医药科技集团股份有限公司 | Method for preparing ethyl 2-(2-aminothiazole-4-yl)-2-methoxyiminoacetate |
| CN107857741A (en) * | 2017-12-15 | 2018-03-30 | 山东金城医药化工有限公司 | The new technique for synthesizing of ainothiazoly loximate |
| CN109796345A (en) * | 2019-01-30 | 2019-05-24 | 青岛科技大学 | A kind of tail gas method of comprehensive utilization of nitrite displacement method production nitromethane |
| CN109796345B (en) * | 2019-01-30 | 2022-02-22 | 青岛科技大学 | Comprehensive utilization method of tail gas generated in nitromethane production by nitrite displacement method |
| CN110372631A (en) * | 2019-07-24 | 2019-10-25 | 东南大学成贤学院 | A kind of preparation method of cefotaxime amide acetaldehyde |
| CN110372631B (en) * | 2019-07-24 | 2021-03-02 | 东南大学成贤学院 | Preparation method of aminothiazoly loximate acetaldehyde |
| CN112457211A (en) * | 2020-11-05 | 2021-03-09 | 丽珠集团新北江制药股份有限公司 | Method for preparing ethyl aminothiazolyloximate intermediate |
| CN112457211B (en) * | 2020-11-05 | 2023-02-28 | 丽珠集团新北江制药股份有限公司 | Method for preparing ethyl aminothiazolyloximate intermediate |
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