CN103992302A - Synthesis process of 2-thiopheneacetic acid - Google Patents
Synthesis process of 2-thiopheneacetic acid Download PDFInfo
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- CN103992302A CN103992302A CN201410266507.1A CN201410266507A CN103992302A CN 103992302 A CN103992302 A CN 103992302A CN 201410266507 A CN201410266507 A CN 201410266507A CN 103992302 A CN103992302 A CN 103992302A
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- thiophene
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—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
Abstract
The invention discloses a synthesis process of 2-thiopheneacetic acid, which comprises the following steps: enabling thiophene as a raw material and formaldehyde react with hydrochloric acid gas to produce 2-chloromethyl thiophene in the presence of an organic solvent; enabling 2-chloromethyl thiophene to react with trimethylsilyl cyanide to generate 2-thiophene acetonitrile in a catalyst condition in the presence of an organic solvent; and generating the thiopheneacetic acid from 2-thiophene acetonitrile in an alkaline condition. The process disclosed by the invention has the positive effects that (1) the required raw materials are relatively simple, and the reaction residues thiophene, an organic solvent, ethanol and dichloromethane can be recycled, thereby greatly reducing the production cost; (2) 2-chloromethyl thiophene reacts in the organic solvent so that chloromethyl thiophene can be stored stably and the danger of explosion is avoided; (3) since trimethylsilyl cyanide is adopted as a cyaniding reagent, the use of highly-toxic substance sodium cyanide is avoided, the reaction yield is increased, the product quality and the safety performance are relatively high, and the industrial production is facilitated; and (4) the reaction conditions are mild, a small quantity of catalyst is used, and the process is simple; and compared with the existing synthesis process, the process disclosed by the invention has obvious economic benefits and environmental benefits.
Description
Technical field
The present invention relates to the synthesis technique of 2-thiophene acetic acid, belong to fine chemical technology field.
Background technology
2-thiophene acetic acid is a kind of important organic synthesis intermediate, is widely used in the synthetic of medical particularly cephalo medicine, as synthetic spectrum antimicrobial drug cefoxitin, Cephaloridine, cefoxitin.Cephalosporin mother nucleus 7-amino-cephalosporanic acid is carried out to structural modification, can improve the anti-microbial activity of medicine.In recent years, external useful 2-thiophene acetic acid is again developed many new cephalosporin antibiotics, has cefetrizole, nitrocefin and Menazone etc.2-thiophene acetic acid also has a wide range of applications in agricultural chemicals, other field of fine chemical of dye well simultaneously
At present 2-thiophene acetic acid method synthetic mainly contain following several: (1) thiophene obtains 2-acetyl thiophene by acetylization reaction; under pressurized conditions, carry out Willgerodt with ethanol, SULPHUR POWDER, ammoniacal liquor again and react generation 2-thiophene ethanamide, hydrolysis obtains 2-thiophene acetic acid again.This building-up reactions need under high pressure be carried out, products obtained therefrom separation difficulty, and target product productive rate is only 20.9%.(2) Chinese patent application 200510047449 discloses a kind of method by thiophene and the synthetic 2-thiophene acetic acid of oxoethanoic acid, although the method is simple, raw materials cost valency is high, and reaction yield is lower and aftertreatment is complicated, is difficult for industrialization and generates.(3) Chinese patent application 201010227870.4 is reported in catalyzer and has lower thiophene and anhydride reaction generation 2-acetyl thiophene, 2-acetyl thiophene generates 2-thiophene oxoethanoic acid with Sodium Nitrite and hydrochloric acid effect again, and 2-thiophene oxoethanoic acid obtains 2-thiophene acetic acid with hydrazine hydrate reduction.The hydrochloric acid that this reaction needed is a large amount of and hydrazine hydrate, post-reaction treatment is complicated, and environment is had to certain influence.(4) at POC1
3under existence, thiophene reacts and obtains 2 thiophene carboxaldehyde with DMF, then reacts with sodium cyanide and trichloromethane, and products obtained therefrom hydrogenation is obtained to 2 thiophene acetonitrile, and hydrolysis obtains 2-thiophene acetic acid again.This synthetic method needs reaction under high pressure and noble metal catalyst, has highly toxic substance sodium cyanide in reactant, and production danger is larger, is unfavorable for suitability for industrialized production.(5) thiophene chloromethylation obtains 2-chloromethyl thiophene, then pressurize under cobalt salt catalysis with carbon monoxide, methyl alcohol, potassium hydroxide and generate 2-thiophene acetic acid ester, through hydrolysis, make 2-thiophene acetic acid again, this synthetic method needs reaction under high pressure and noble metal catalyst equally, and intermediate product 2-chloromethyl thiophene is a kind of lachrymator, unstable, when airtight, there is the danger of blast.
Summary of the invention
The object of the present invention is to provide a kind of technique advantages of simple, pollute littlely, cost is low, is conducive to the 2-thiophene acetic acid synthesis technique of suitability for industrialized production.
Realizing the technical scheme that the object of the invention takes is:
The present invention be take thiophene as raw material, mainly comprises the following steps:
(1), under organic solvent exists, thiophene reacts with formaldehyde, hydrogen chloride gas produces 2-chloromethyl thiophene;
(2) 2-chloromethyl thiophene, under organic solvent exists, reacts under catalyzer condition with trimethylsilyl cyanide and generates 2 thiophene acetonitrile;
(3) 2 thiophene acetonitrile, under alkaline condition, generates 2-thiophene acetic acid.
the reaction equation of the synthetic 2-thiophene acetic acid of the present invention is as follows:
?
concrete steps of the present invention are:
Step is the preparation of 2-chloromethyl thiophene 1.: first paraformaldehyde is dissolved among 37% hydrochloric acid, being heated to 60-70 ℃ makes paraformaldehyde be depolymerized to formaldehyde solution, then thiophene is dissolved in organic solvent, stirring is cooled between 0-5 ℃, pass into hydrogen chloride gas, in this temperature range, above-mentioned formaldehyde hydrochloric acid soln is slowly dripped afterwards into, drip complete insulation reaction 5 hours; React in backward system and stir with frozen water, standing separation organic phase, organic phase is with stand-by after aqueous sodium carbonate washing; Organic solvent used is 2,3-adipic ketone or butanone;
Step is synthesizing of 2 thiophene acetonitrile 2.: trimethylsilyl cyanide, catalyzer are put into flask, be warming up to 70 ℃, above-mentioned chloromethyl thiophene mixed solution is slowly splashed into, dropwise insulation reaction 6 hours, the cooling a little rear standing organic phase that separates, washes three times; First air distillation thiophene and organic solvent, then under 105-110 ℃, 13mmHg, cut is collected in vacuum distilling, obtains 2 thiophene acetonitrile; Used catalyst is fluorinated quaternary ammonium salt;
Step is synthesizing of 2-thiophene acetic acid 3.: above-mentioned 2 thiophene acetonitrile is dissolved in ethanol, slowly drip into the aqueous sodium hydroxide solution under reflux state, drip and finish again back flow reaction 3 hours, afterwards recovery of alcohol distillation, filtrate is being adjusted pH value to 1-2 with hydrochloric acid below 10 ℃, has suspended solid to generate; Then filter to obtain faint yellow solid thing 2-thiophene acetic acid crude product, then through obtaining 2-thiophene acetic acid crystal after sherwood oil recrystallization.
The step 1. mol ratio of middle thiophene, paraformaldehyde, hydrogen chloride gas is 1:1:1.3-1.5, and temperature of reaction is 0 ℃; Organic solvent used is 2,3-adipic ketone; Step 2. in the quality of trimethylsilyl cyanide used be 1.1-1.2 times of the first step thiophene quality; The step 3. mass ratio of middle 2 thiophene acetonitrile, ethanol, sodium hydroxide is 1:1:0.5-0.6; Reflux temperature is 84-86 ℃.
positively effect of the present invention is:(1) required starting material are comparatively cheap, and the thiophene, organic solvent, ethanol, the methylene dichloride that react remaining can reclaim and re-use, and production cost reduces greatly; (2) 2-chloromethyl thiophene is reacted in organic solvent, thereby make chloromethyl thiophene can stablize storage, do not have the danger of blast; (3) select trimethylsilyl cyanide as cyanating reagent, thereby avoid using highly toxic substance sodium cyanide, not only improved reaction yield, quality product, and also safety performance is also relatively high, is beneficial to suitability for industrialized production; (4) reaction conditions is gentle, and catalyst levels is few, and technique is simple; Compare with existing synthesis technique, the present invention has obvious economic benefit and environmental benefit.
Embodiment
It is further to set forth of the present invention that concrete embodiment is provided below, but embodiment does not limit the scope of the invention.
Embodiment 1
(1) preparation of 2-chloromethyl thiophene: first 30 grams of paraformaldehydes are dissolved among 137g 37% hydrochloric acid, heating makes paraformaldehyde be depolymerized to formaldehyde, then 84g thiophene is dissolved in 200g butanone, stirring is cooled to and between 0-5 ℃, passes into hydrogen chloride gas 54.5g, in this temperature range, above-mentioned formaldehyde hydrochloric acid soln is slowly dripped simultaneously into, drip complete insulation reaction 5 hours.In the complete system of reaction, with frozen water, stir, divide and get organic phase, organic phase is with stand-by after aqueous sodium carbonate washing.
(2) 2 thiophene acetonitrile is synthetic: 100 grams of trimethylsilyl cyanides, 5g tetrabutyl fluoride amine are put into 500mL four-hole boiling flask, be warming up to 70 ℃, above-mentioned chloromethyl thiophene mixed solution is slowly splashed into.Dropwise insulation reaction 6 hours, the cooling a little rear standing organic phase that separates, organic phase washing three times.First air distillation thiophene and organic solvent, reclaim thiophene 10g, and vacuum distilling is collected 105-110 ℃ of (13mmHg) cuts and obtained 2 thiophene acetonitrile 87.2g,, content 76.4%.(1) (2) step total recovery 61.5%.
(3) 2-thiophene acetic acid is synthetic: above-mentioned 2 thiophene acetonitrile 87.2g is dissolved in ethanol 90g, slowly drip into the aqueous solution of the 31g sodium hydroxide under reflux state, drip and finish back flow reaction 3 hours (having a large amount of ammonia taste γ-ray emissions in reaction process) again, reclaim distilled spirit.Filtrate is being adjusted pH value to 1-2 with hydrochloric acid below 10 ℃, and filtrate is being adjusted pH value to 1-2 with hydrochloric acid below 10 ℃, has suspended solid to generate.Then filter to obtain faint yellow solid thing 2-thiophene acetic acid crude product, then through obtaining 2-thiophene acetic acid crystal 73.2g after sherwood oil recrystallization, yield is 95.2%, content 99.2%.
Embodiment 2
(1) preparation of 2-chloromethyl thiophene: first 30 grams of paraformaldehydes are dissolved among 137g 37% hydrochloric acid, heating makes paraformaldehyde be depolymerized to formaldehyde.Then 84g thiophene is dissolved in 200g 2,3-adipic ketone, stirs to be cooled between 0-5 ℃ and pass into hydrogen chloride gas 53.6g, in this temperature range, above-mentioned formaldehyde hydrochloric acid soln is slowly dripped simultaneously into, drip complete insulation reaction 5 hours.In the complete system of reaction, with frozen water, stir, divide and get organic phase.Organic phase is with stand-by after aqueous sodium carbonate washing.
(2) 2 thiophene acetonitrile is synthetic: 100 grams of trimethylsilyl cyanides, 5g tetrabutyl fluoride amine are put into 500mL four-hole boiling flask, be warming up to 70 ℃, above-mentioned chloromethyl thiophene mixed solution is slowly splashed into.Dropwise insulation reaction 6 hours, the cooling a little rear standing organic phase that separates, organic phase washing three times.First air distillation thiophene and organic solvent, reclaim thiophene 9.2g, and vacuum distilling is collected 105-110 ℃ of (13mmHg) cuts and obtained 2 thiophene acetonitrile 93.9g, content 76.3%.(1) (2) step total recovery 65.4%.
(3) 2-thiophene acetic acid is synthetic: above-mentioned 2 thiophene acetonitrile 93.9g is dissolved in ethanol 90g, slowly drip into the aqueous solution of the 34g sodium hydroxide under reflux state, drip and finish back flow reaction 3 hours (having a large amount of ammonia taste γ-ray emissions in reaction process) again, reclaim distilled spirit.Filtrate is being adjusted pH value to 1-2 with hydrochloric acid below 10 ℃, and filtrate is being adjusted pH value to 1-2 with hydrochloric acid below 10 ℃, has suspended solid to generate.Then filter to obtain faint yellow solid thing 2-thiophene acetic acid crude product, then through obtaining 2-thiophene acetic acid crystal 78.8g after sherwood oil recrystallization, yield is 95.3%, content 99.4%.
Claims (3)
1. a 2-thiophene acetic acid synthesis technique, it is to take thiophene as raw material, by following steps, is realized:
(1), under organic solvent exists, thiophene reacts with formaldehyde, hydrogen chloride gas produces 2-chloromethyl thiophene;
(2) 2-chloromethyl thiophene, under organic solvent exists, reacts under catalyzer condition with trimethylsilyl cyanide and generates 2 thiophene acetonitrile;
(3) 2 thiophene acetonitrile, under alkaline condition, generates 2-thiophene acetic acid;
Reaction equation is as follows:
?
。
2. 2-thiophene acetic acid synthesis technique according to claim 1, is characterized in that:
Step is the preparation of 2-chloromethyl thiophene 1.: first paraformaldehyde is dissolved among 37% hydrochloric acid, being heated to 60-70 ℃ makes paraformaldehyde be depolymerized to formaldehyde solution, then thiophene is dissolved in organic solvent, stirring is cooled between 0-5 ℃, pass into hydrogen chloride gas, in this temperature range, above-mentioned formaldehyde hydrochloric acid soln is slowly dripped afterwards into, drip complete insulation reaction 5 hours; React in backward system and stir with frozen water, standing separation organic phase, organic phase is with stand-by after aqueous sodium carbonate washing; Organic solvent used is 2,3-adipic ketone or butanone;
Step is synthesizing of 2 thiophene acetonitrile 2.: trimethylsilyl cyanide, catalyzer are put into flask, be warming up to 70 ℃, above-mentioned chloromethyl thiophene mixed solution is slowly splashed into, dropwise insulation reaction 6 hours, the cooling a little rear standing organic phase that separates, washes three times; First air distillation thiophene and organic solvent, then under 105-110 ℃, 13mmHg, cut is collected in vacuum distilling, obtains 2 thiophene acetonitrile; Used catalyst is fluorinated quaternary ammonium salt;
Step is synthesizing of 2-thiophene acetic acid 3.: above-mentioned 2 thiophene acetonitrile is dissolved in ethanol, slowly drip into the aqueous sodium hydroxide solution under reflux state, drip and finish again back flow reaction 3 hours, afterwards recovery of alcohol distillation, filtrate is being adjusted pH value to 1-2 with hydrochloric acid below 10 ℃, has suspended solid to generate; Then filter to obtain faint yellow solid thing 2-thiophene acetic acid crude product, then through obtaining 2-thiophene acetic acid crystal after sherwood oil recrystallization.
3. 2-thiophene acetic acid synthesis technique according to claim 2, is characterized in that: the step 1. mol ratio of middle thiophene, paraformaldehyde, hydrogen chloride gas is 1:1:1.3-1.5, and temperature of reaction is 0 ℃; Organic solvent used is 2,3-adipic ketone; Step 2. in the quality of trimethylsilyl cyanide used be 1.1-1.2 times of the first step thiophene quality; The step 3. mass ratio of middle 2 thiophene acetonitrile, ethanol, sodium hydroxide is 1:1:0.5-0.6; Reflux temperature is 84-86 ℃.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104327040A (en) * | 2014-10-11 | 2015-02-04 | 华东师范大学 | Synthetic method for 2-thiopheneacetic acid |
| CN106518839A (en) * | 2017-01-11 | 2017-03-22 | 鲁东大学 | Green preparation technology of 2-thiopheneacetic acid |
| CN109843862A (en) * | 2016-10-26 | 2019-06-04 | 石原产业株式会社 | 3- methyl -2-Thiophene Carboxylic Acid manufacturing method |
| CN113896709A (en) * | 2021-11-22 | 2022-01-07 | 南京一苇医药科技有限公司 | Synthetic method of benzothiophene-3-acetic acid |
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| CN1511148A (en) * | 2001-05-22 | 2004-07-07 | ��ŵ�Ѻϳ�ʵ���� | Chloromethylation of thiophene |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1511148A (en) * | 2001-05-22 | 2004-07-07 | ��ŵ�Ѻϳ�ʵ���� | Chloromethylation of thiophene |
Non-Patent Citations (2)
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| 李正杰等: "三甲基氰硅烷的合成及其研究进展", 《精细与专用化学品》, vol. 21, no. 12, 31 December 2013 (2013-12-31), pages 35 - 37 * |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104327040A (en) * | 2014-10-11 | 2015-02-04 | 华东师范大学 | Synthetic method for 2-thiopheneacetic acid |
| CN109843862A (en) * | 2016-10-26 | 2019-06-04 | 石原产业株式会社 | 3- methyl -2-Thiophene Carboxylic Acid manufacturing method |
| CN109843862B (en) * | 2016-10-26 | 2021-10-29 | 石原产业株式会社 | Process for producing 3-methyl-2-thiophenecarboxylic acid |
| CN106518839A (en) * | 2017-01-11 | 2017-03-22 | 鲁东大学 | Green preparation technology of 2-thiopheneacetic acid |
| CN113896709A (en) * | 2021-11-22 | 2022-01-07 | 南京一苇医药科技有限公司 | Synthetic method of benzothiophene-3-acetic acid |
| CN113896709B (en) * | 2021-11-22 | 2023-02-28 | 南京一苇医药科技有限公司 | Synthetic method of benzothiophene-3-acetic acid |
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Application publication date: 20140820 |