CN105503792A - Method for synthesizing (Z)-2-(alpha-methoxyimino)furanylacetic acid ammonium - Google Patents
Method for synthesizing (Z)-2-(alpha-methoxyimino)furanylacetic acid ammonium Download PDFInfo
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- CN105503792A CN105503792A CN201510968952.7A CN201510968952A CN105503792A CN 105503792 A CN105503792 A CN 105503792A CN 201510968952 A CN201510968952 A CN 201510968952A CN 105503792 A CN105503792 A CN 105503792A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/09—Geometrical isomers
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Abstract
The invention belongs to the technical field of medical intermediate preparation, and particularly relates to a method for synthesizing (Z)-2-(alpha-methoxyimino)furanylacetic acid ammonium. The method comprises the following steps that 1, 2-oxo-2-furanylacetic acid and heavy metal salt are dissolved in water, an aqueous methoxyamine solution or aqueous methoxyamine salt solution is added at the temperature of 0 DEG C-10 DEG C, and the pH is regulated to 2.5-3.5; 2, heat preservation is performed for 2-7 h at the temperature of 5 DEG C-10 DEG C, and a 2-(alpha-methoxyimino)furanylacetic acid solution is obtained; 3, the pH of the 2-(alpha-methoxyimino)furanylacetic acid solution is regulated to 0.1-1.5 by adopting inorganic acid, the temperature is controlled at 15 DEG C-25 DEG C, extraction is performed through organic solvent, and organic phases are combined; 4, ammonia gas or liquid ammonia is introduced into the organic phases at the temperature of 0 DEG C-10 DEG C, the pH is regulated to 6.5-7.5, heat preservation is performed for 0.5-1.5 h to obtain a crude product, and after decoloration, concentration and crystallization are performed, the product is obtained. The method is high in yield and good in product quality.
Description
Technical field
The invention belongs to technical field of medical intermediate preparation, be specifically related to a kind of method of synthesis (Z)-2-(α-methoxy imino) furans ammonium acetate.
Background technology
(Z)-2-(α-methoxy imino) furans ammonium acetate or 2-(Z)-methoxy imino-2-furans ammonium acetate, also claiming SMIA, is the key intermediate for the synthesis of cefuroxime axetil.Due to thermodynamics or dynamic (dynamical) impact, in the process of synthesis (Z)-2-(α-methoxy imino) furans acetic acid, the ratio of by product (E)-2-(α-methoxy imino) furans acetic acid accounts for about 15%, cause the waste of raw material, the product simultaneously generated not easily is refined, a large amount of costs can be increased, be unfavorable for producing.
The production of current SMIA has the improvement of much technique, but in the source controlling trans generation, yet there are no pertinent literature report, and which dictates that quality and the yield of produced product.
Some heavy metal ion contains unoccupied orbital, complex compound can be formed with some parts, when the part containing two ligating atom and complex, the effect of fixing heavy metal ion can be played, simultaneously heavy metal ion other unoccupied orbitals can with another kind of raw material complexing, several atom forms an intermediate two dimensional structure, after overcoming this activation energy, and the product required for main generation.
Summary of the invention
For the deficiencies in the prior art, the object of this invention is to provide a kind of method of synthesis (Z)-2-(α-methoxy imino) furans ammonium acetate, adopt the method that the heavy metal ion orthoselection containing unoccupied orbital generates, improve quality and the yield of product.
The method of synthesis of the present invention (Z)-2-(α-methoxy imino) furans ammonium acetate, comprises the steps:
(1) 2-oxo-2-furyl acetic acid and heavy metallic salt are dissolved in water, at 0 ~ 10 DEG C, add the Vasoxyl aqueous solution or Vasoxyl salt brine solution, regulate pH to 2.5 ~ 3.5;
(2) solution that step (1) is obtained is incubated 2 ~ 7h at 5 ~ 10 DEG C, obtains 2-(α-methoxy imino) furans acetic acid solution;
(3) adopt mineral acid to regulate pH to 0.1 ~ 1.5 of 2-(α-methoxy imino) furans acetic acid solution, control temperature 15 ~ 25 DEG C, with organic solvent extraction, merge organic phase;
(4) at 0 ~ 10 DEG C, ammonia or liquefied ammonia are passed into organic phase, regulate pH to 6.5 ~ 7.5, after insulation 0.5 ~ 1.5h crude product, after decolouring, concentrated, crystallization product.
Wherein:
In step (1), described heavy metallic salt is the one in soluble copper salt, soluble zinc salt or soluble manganese salt.
In step (1), the consumption of described heavy metallic salt is 0.08 ~ 0.12% of 2-oxo-2-furyl quality of acetic acid.
In step (1), described methoxy amine salt is methoxamine hydrochloride.
In step (1), the described Vasoxyl aqueous solution or the massfraction of Vasoxyl salt brine solution are 5 ~ 20%.
In step (1), when adding the Vasoxyl aqueous solution, adopt acid for adjusting pH to 2.5 ~ 3.5; The acid adopted is the one in hydrochloric acid, sulfuric acid or phosphoric acid.
In step (1), when adding Vasoxyl salt brine solution, alkali is adopted to regulate pH to 2.5 ~ 3.5; The alkali adopted is the one in the oxyhydroxide of basic metal or alkaline-earth metal, carbonate or supercarbonate.
In step (1), described 2-oxo-2-furyl acetic acid and the mol ratio of Vasoxyl or methoxy amine salt are 1:1.2 ~ 1.5.
In step (2), described 2-(α-methoxy imino) furans acetic acid solution, (Z)-2-(α-methoxy imino) furans acetic acid and (E)-2-(α-methoxy imino) furans acetic acid content ratio are 95 ~ 95.5:4.5 ~ 5.
The method of described synthesis (Z)-2-(α-methoxy imino) furans ammonium acetate, chemical equation is as follows:
In sum, beneficial effect of the present invention is as follows:
The method that the present invention adopts the heavy metal ion orthoselection containing unoccupied orbital to generate, productive rate is high, good product quality, decrease the generation of (E)-2-(α-methoxy imino) furans ammonium acetate, solve traditional technology wastage of material large, the difficult problem that production cost is high, raw material availability reaches 95%, improve about 10% than traditional technology, greatly reduce the wasting of resources, reduce production cost.
Embodiment
Below in conjunction with embodiment, the present invention will be further described.
Embodiment 1
(1) 40g2-oxo-2-furyl acetic acid and 0.04g cupric sulfate pentahydrate are dissolved in 300mL water, at 0 DEG C, add the 100g Vasoxyl aqueous solution, adopt dilute sulphuric acid to regulate pH to 3.5;
The massfraction of the described Vasoxyl aqueous solution is 17%;
(2) solution that step (1) is obtained is incubated 4.5h at 8 DEG C, obtains 2-(α-methoxy imino) furans acetic acid solution; Liquid Detection, (Z)-2-(α-methoxy imino) furans acetic acid: (E)-2-(α-methoxy imino) furans acetic acid is 95.1:4.9;
(3) adopt dilute sulphuric acid to regulate the pH to 0.8 of 2-(α-methoxy imino) furans acetic acid solution, control temperature 20 DEG C, with dichloromethane extraction, merge organic phase;
(4) at 5 DEG C, ammonia is passed into organic phase, regulates pH to 7.0, after insulation 1h crude product, after decolouring, concentrated, crystallization product 48.9g, yield is 92%.
Product checking result:
Outward appearance: off-white color crystalline powder;
Differentiate (HPLC): 99.91%;
Moisture (K.F.) :≤0.50%;
Transmittance :≤0.15%;
Trans-isomer(ide) :≤0.020%.
Embodiment 2
(1) 40g2-oxo-2-furyl acetic acid and 0.032g manganous chloride are dissolved in 300mL water, at 5 DEG C, add the 160g methoxamine hydrochloride aqueous solution, adopt potassium hydroxide to regulate pH to 3.0;
The massfraction of the described methoxamine hydrochloride aqueous solution is 20%;
(2) solution that step (1) is obtained is incubated 2h at 10 DEG C, obtains 2-(α-methoxy imino) furans acetic acid solution; Liquid Detection, (Z)-2-(α-methoxy imino) furans acetic acid: (E)-2-(α-methoxy imino) furans acetic acid is 95.0:5.0;
(3) adopt dilute hydrochloric acid to regulate the pH to 0.1 of 2-(α-methoxy imino) furans acetic acid solution, control temperature 25 DEG C, with dichloromethane extraction, merge organic phase;
(4) at 0 DEG C, ammonia is passed into organic phase, regulates pH to 7.5, after insulation 1.5h crude product, after decolouring, concentrated, crystallization product 47.4g, yield is 89%.
Product checking result:
Outward appearance: off-white color crystalline powder;
Differentiate (HPLC): 99.90%;
Moisture (K.F.) :≤0.50%;
Transmittance :≤0.15%;
Trans-isomer(ide) :≤0.031%.
Embodiment 3
(1) 40g2-oxo-2-furyl acetic acid and 0.048g zinc sulfate are dissolved in 300mL water, at 10 DEG C, add the 392g Vasoxyl aqueous solution, adopt dilute sulphuric acid to regulate pH to 2.5;
The massfraction of the described Vasoxyl aqueous solution is 5%;
(2) solution that step (1) is obtained is incubated 7h at 5 DEG C, obtains 2-(α-methoxy imino) furans acetic acid solution; Liquid Detection (Z)-2-(α-methoxy imino) furans acetic acid: (E)-2-(α-methoxy imino) furans acetic acid is 95.5:4.5,
(3) adopt dilute phosphoric acid to regulate the pH to 1.5 of 2-(α-methoxy imino) furans acetic acid solution, control temperature 15 DEG C, with dichloromethane extraction, merge organic phase;
(4) at 10 DEG C, liquefied ammonia is passed into organic phase, regulates pH to 6.5, after insulation 0.5h crude product, after decolouring, concentrated, crystallization product 48.0g, yield is 90%.
Product checking result:
Outward appearance: off-white color crystalline powder;
Differentiate (HPLC): 99.93%;
Moisture (K.F.) :≤0.50%;
Transmittance :≤0.16%;
Trans-isomer(ide) :≤0.028%.
Claims (9)
1. synthesize a method for (Z)-2-(α-methoxy imino) furans ammonium acetate, it is characterized in that: comprise the steps:
(1) 2-oxo-2-furyl acetic acid and heavy metallic salt are dissolved in water, at 0 ~ 10 DEG C, add the Vasoxyl aqueous solution or Vasoxyl salt brine solution, regulate pH to 2.5 ~ 3.5;
(2) solution that step (1) is obtained is incubated 2 ~ 7h at 5 ~ 10 DEG C, obtains 2-(α-methoxy imino) furans acetic acid solution;
(3) adopt mineral acid to regulate pH to 0.1 ~ 1.5 of 2-(α-methoxy imino) furans acetic acid solution, control temperature 15 ~ 25 DEG C, with organic solvent extraction, merge organic phase;
(4) at 0 ~ 10 DEG C, ammonia or liquefied ammonia are passed into organic phase, regulate pH to 6.5 ~ 7.5, after insulation 0.5 ~ 1.5h crude product, after decolouring, concentrated, crystallization product.
2. the method for synthesis according to claim 1 (Z)-2-(α-methoxy imino) furans ammonium acetate, it is characterized in that: in step (1), described heavy metallic salt is the one in soluble copper salt, soluble zinc salt or soluble manganese salt.
3. the method for synthesis according to claim 1 (Z)-2-(α-methoxy imino) furans ammonium acetate, it is characterized in that: in step (1), the consumption of described heavy metallic salt is 0.08 ~ 0.12% of 2-oxo-2-furyl quality of acetic acid.
4. the method for synthesis according to claim 1 (Z)-2-(α-methoxy imino) furans ammonium acetate, it is characterized in that: in step (1), described methoxy amine salt is methoxamine hydrochloride.
5. the method for synthesis according to claim 1 (Z)-2-(α-methoxy imino) furans ammonium acetate, it is characterized in that: in step (1), the described Vasoxyl aqueous solution or the massfraction of Vasoxyl salt brine solution are 5 ~ 20%.
6. the method for synthesis according to claim 1 (Z)-2-(α-methoxy imino) furans ammonium acetate, is characterized in that: in step (1), when adding the Vasoxyl aqueous solution, adopts acid for adjusting pH to 2.5 ~ 3.5; The acid adopted is the one in hydrochloric acid, sulfuric acid or phosphoric acid.
7. the method for synthesis according to claim 1 (Z)-2-(α-methoxy imino) furans ammonium acetate, is characterized in that: in step (1), when adding Vasoxyl salt brine solution, adopts alkali to regulate pH to 2.5 ~ 3.5; The alkali adopted is the one in the oxyhydroxide of basic metal or alkaline-earth metal, carbonate or supercarbonate.
8. the method for synthesis according to claim 1 (Z)-2-(α-methoxy imino) furans ammonium acetate, it is characterized in that: in step (1), described 2-oxo-2-furyl acetic acid and the mol ratio of Vasoxyl or methoxy amine salt are 1:1.2 ~ 1.5.
9. the method for synthesis according to claim 1 (Z)-2-(α-methoxy imino) furans ammonium acetate, it is characterized in that: in step (2), described 2-(α-methoxy imino) furans acetic acid solution, (Z)-2-(α-methoxy imino) furans acetic acid and (E)-2-(α-methoxy imino) furans acetic acid content ratio are 95 ~ 95.5:4.5 ~ 5.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107903226A (en) * | 2017-11-29 | 2018-04-13 | 中国科学院长春应用化学研究所 | A kind of preparation method of cis furan ammonium salt |
| CN110590719A (en) * | 2019-08-15 | 2019-12-20 | 安徽金禾实业股份有限公司 | Green method for preparing 2-furoic acid |
| CN114133338A (en) * | 2021-11-17 | 2022-03-04 | 安徽金轩科技有限公司 | Device and method for recovering methoxyamine from oximation wastewater in production of furan ammonium salt |
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| CN101357911A (en) * | 2008-09-19 | 2009-02-04 | 江苏爱利思达清泉化学有限公司 | Method for synthesizing (z)-2-(alpha-methoxyimino)furan-ammonium acetate |
| CN101538255A (en) * | 2009-04-02 | 2009-09-23 | 浙江拓普药业股份有限公司 | Preparing method of 2-methoxy imino group 2-furan ammonium acetate |
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2015
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107903226A (en) * | 2017-11-29 | 2018-04-13 | 中国科学院长春应用化学研究所 | A kind of preparation method of cis furan ammonium salt |
| CN107903226B (en) * | 2017-11-29 | 2021-12-14 | 中国科学院长春应用化学研究所 | Preparation method of cis-furan ammonium salt |
| CN110590719A (en) * | 2019-08-15 | 2019-12-20 | 安徽金禾实业股份有限公司 | Green method for preparing 2-furoic acid |
| CN110590719B (en) * | 2019-08-15 | 2022-04-19 | 安徽金禾实业股份有限公司 | Green method for preparing 2-furoic acid |
| CN114133338A (en) * | 2021-11-17 | 2022-03-04 | 安徽金轩科技有限公司 | Device and method for recovering methoxyamine from oximation wastewater in production of furan ammonium salt |
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