CN110294734A - A kind of preparation method of 2- aminothiophene -3,4- dicarboxylic acid derivatives - Google Patents
A kind of preparation method of 2- aminothiophene -3,4- dicarboxylic acid derivatives Download PDFInfo
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- CN110294734A CN110294734A CN201910583126.9A CN201910583126A CN110294734A CN 110294734 A CN110294734 A CN 110294734A CN 201910583126 A CN201910583126 A CN 201910583126A CN 110294734 A CN110294734 A CN 110294734A
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- Prior art keywords
- aminothiophene
- dicarboxylic acid
- acid derivatives
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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
- C07D333/26—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 hetero atoms or with 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The present invention relates to a kind of preparation methods of 2- aminothiophene -3,4- dicarboxylic acid derivatives.Mainly solve existing preparation method purifying need to using column chromatograph, can not large-scale production the technical issues of.Preparation method includes (1) by pyruvate, and cyanoacetate, sulphur powder is reacted in the presence of alkali and solvent, obtains reaction solution；(2) obtained reaction solution is diluted with ethyl acetate, successively uses aqueous citric acid solution, sodium-chloride water solution, water washing obtains 2- aminothiophene -3,4- dicarboxylic acid derivatives crude product solution；(3) obtained 2- aminothiophene -3,4- dicarboxylic acid derivatives crude product solution is cooled to 0~-20 DEG C, starts to be passed through dry hydrogen chloride gas, until solid is all precipitated；(4) filter cake being obtained by filtration washed once with 0~-20 DEG C of ethyl acetate, with saturated sodium bicarbonate tune pH to 7-8；(5) liquid separation, collects organic phase, and organic phase is washed to obtain 2- aminothiophene -3,4- dicarboxylic acid derivatives sterling solution with aqueous solution；(6) it removes ethyl acetate and obtains 2- aminothiophene -3,4- dicarboxylic acid derivatives sterling.
Description
Technical field
The present invention relates to a kind of preparation methods of 2- aminothiophene -3,4- dicarboxylic acid derivatives.This method has synthesis
Route is short, easy to operate, feature easy to industrialized production.
Background technique
2- aminothiophene -3,4- dicarboxylic acid derivatives, structure are shown below, and are among the important chemicals of one kind
Body is mainly used for synthesizing thiofuran and pyrimidine derivatives.
Thienopyrimidine derivative is a kind of with good sterilization, antimycotic, the fused heterocyclic compound of anti-tumor activity, spy
It is not that can be used for inhibiting acetyl-CoA carboxylase (ACC) and for mutant epidermal growth factor receptor tyrosine kinase (EGFR-
TK) inhibitor, treat or prevent disease that mammal, the especially mankind are adjusted in acetyl-CoA carboxylase (ACC) and
There is important purposes in terms of for treating EGFR related disease.
Gewald reaction is a kind of important method for rapidly and efficiently synthesizing 2- amido thiophenes.ZL
201811165670.3 use cyclic ketones, and nitrile and sulphur are raw material to prepare 2- aminothiophene class compound, and ketone used is confined to cyclic ketones
And aromatic ketone；Patent WO2013024291, US2014/309222 and document tetrahedron flash report (Tetrahedron
Letters, 2015,56,4486-4489) 2- aminothiophene -3,4- dicarboxylic acid methyl ester and aminothiophene -3 2- are reported,
The synthesis of 4- dicarboxylic acid ethyl ester；Patent US2018/170948 and document organic chemistry communication (Organic Letters,
2011,13,38-41) with organic chemistry periodical (Journal of Organic Chemistry, 2012,77,8167-8173)
The synthesis for reporting 2- aminothiophene -3- Ethyl formate -4- methyl formate, in these reports, the purifying of finished product needs logical
Column chromatography is crossed to complete, cannot achieve large-scale production.In addition to this, without other document reports.
Summary of the invention
The present invention provides a kind of preparation method of 2- aminothiophene -3,4- dicarboxylic acid derivatives, this method has synthesis
Route is short, easy to operate, feature easy to industrialized production.
The present invention relates to specific reaction route it is as follows:
Wherein: R1、R2It is one of hydrogen atom, methyl, ethyl, n-propyl, isopropyl or tert-butyl, wherein R1With R2It can be with
It is same or different.
Specifically includes the following steps:
(1) by pyruvate, cyanoacetate, sulphur powder is with molar ratio 1:1.05:1.2, in the presence of alkali and solvent, in certain temperature
Under reacted, obtain reaction solution；
(2) obtained reaction solution is diluted with ethyl acetate, successively uses 10% aqueous citric acid solution of mass percentage concentration,
10% sodium-chloride water solution of mass percentage concentration, water washing obtain 2- aminothiophene -3,4- dicarboxylic acid derivatives crude product solution；
(3) obtained 2- aminothiophene -3,4- dicarboxylic acid derivatives crude product solution is cooled to 0~-20 DEG C, preferably -20 DEG C
Start to be passed through dry hydrogen chloride gas, until solid is all precipitated；
(4) by the filter cake being obtained by filtration with 0~-20 DEG C, preferably -20 DEG C of ethyl acetate be washed once, with saturated sodium bicarbonate tune
PH to 7-8；
(5) liquid separation, collects organic phase, and organic phase is washed with water to obtain 2- aminothiophene -3,4- dicarboxylic acid derivatives sterling molten
Liquid；
(6) it removes ethyl acetate and obtains 2- aminothiophene -3,4- dicarboxylic acid derivatives sterling.
Alkali used in step (1) is selected from following one or several kinds: sodium carbonate, potassium carbonate, sodium ethoxide, potassium ethoxide, uncle
Butanol potassium, sodium tert-butoxide, sodium hydroxide, triethylamine, diethylamine, ammonium hydroxide, diisopropylamine or ethanol amine；It is preferred that triethylamine.Institute
Solvent is selected from one of DMF, dioxane, tetrahydrofuran, normal propyl alcohol, isopropanol, the tert-butyl alcohol, ethyl alcohol, methanol or water
Or several, preferably DMF.Range of reaction temperature is -20~70 DEG C.
Beneficial effects of the present invention: the present invention reacts derivative to construct 2- aminothiophene -3,4- dicarboxylic acids using Gewald
Object uses dry hydrogen chloride gas to purify in a manner of at salt to product for the first time, have it is easy to operate, be easy to be advised greatly
Mould production.
Specific embodiment
The present invention is further detailed according to specific embodiment, the present invention is not limited only to these embodiments.
Embodiment 1
1.0 kg methyl pyruvates, 1.0 kg DMF are added in reaction kettle, the 1.5 kg cyanoacetic acid tert-butyl esters are added 0.38
The high-purity sulphur powder of kg opens stirring, stirs 30 mins at room temperature.1.1 kg triethylamines, 1.0 kg DMF are dissolved, are slowly dripped
It adds in reaction kettle.Control temperature of reaction system is no more than 60 DEG C during being added dropwise.After adding, temperature of reaction kettle is warming up to 70
DEG C, it reacts 12 hours.It is cooled to room temperature, is diluted with 10L ethyl acetate, successively use 10% aqueous citric acid solution of mass percentage concentration
10L, mass percentage concentration 10% sodium-chloride water solution 10L, water 10L washing, organic phase is 2 hours dry with anhydrous magnesium sulfate, mistake
Filter.It controls reactor temperature (- 20 DEG C), starts to be passed through dry hydrogen chloride gas, until being precipitated without solid, in -20 DEG C
Under continue stirring 1 hour, filtering, collect solid, by obtained solid with 10L ethyl acetate disperse, be added quality percentage
10% sodium bicarbonate aqueous solution of concentration adjusts pH to 7-8, and liquid separation, organic phase is washed once with 10L, dry with anhydrous magnesium sulfate, dense
Contracting obtains 1.52 Kg of solid product, yield 60%.1H NMR(CDCl3, 400 MHz, ppm):
7.90 (s, 1H), 6.99 (s, 2H), 3.89 (s, 3H), 1.38 (s, 9H)。
Embodiment 2
Concrete operations are methyl pyruvate and methyl cyanoacetate with 1. reaction mass of embodiment.
Yield 80%.1H NMR(CDCl3, 400 MHz, ppm): 8.27 (s, 1H), 7.46 (s, 2H), 3.90
(s, 6H)。
Embodiment 3
Concrete operations are ethyl pyruvate and ethyl cyanoacetate with 1. reaction mass of embodiment.
Yield 85%.1H NMR(CDCl3, 400 MHz, ppm): 8.27 (s, 1H), 7.46 (s, 2H), 4.35
(m, 4H), 1.30 (t, 6H).
Embodiment 4
Concrete operations are acetone isopropyl propionate and cyanoacetic acid isopropyl ester with 1. reaction mass of embodiment.
Yield 82%.1H NMR(CDCl3, 400 MHz, ppm): 8.27 (s, 1H), 7.46 (s, 2H), 5.24
(m, 2H), 1.39 (d, 12H).
Embodiment 5
Concrete operations are acetone tert-butyl acrylate and the cyanoacetic acid tert-butyl ester with 1. reaction mass of embodiment.
Yield 75%.1H NMR(CDCl3, 400 MHz, ppm): 8.27 (s, 1H), 7.46 (s, 2H), 1.42
(s, 18H)。
Embodiment 6
Concrete operations are acetone tert-butyl acrylate and methyl cyanoacetate with 1. reaction mass of embodiment.
Yield 69%.1H NMR(CDCl3, 400 MHz, ppm): 8.27 (s, 1H), 7.46 (s, 2H), 3.90
(s,3H), 1.42 (s, 9H)。
Embodiment 7
Concrete operations are acetone isopropyl propionate and the cyanoacetic acid tert-butyl ester with 1. reaction mass of embodiment.
Yield 70%.1H NMR(CDCl3, 400 MHz, ppm): 8.27 (s, 1H), 7.46 (s, 2H), 5.24
(m,1H), 1.42 (s, 9H), 1.39(d, 6H)。
Embodiment 8
Concrete operations are ethyl pyruvate and the cyanoacetic acid tert-butyl ester with 1. reaction mass of embodiment.
Yield 66%.1H NMR(CDCl3, 400 MHz, ppm): 8.27 (s, 1H), 7.48 (s, 2H), 4.35
(m,2H), 1.42 (s, 9H), 1.30(t, 3H)。
Embodiment 9
Concrete operations are pyruvic acid and cyanoacetic acid with 1. reaction mass of embodiment.
Yield 40%.1H NMR(CDCl3, 400 MHz, ppm): 12.75 (s, 2H), 8.40 (s, 1H), 7.46
(s, 2H)。
Claims (5)
1. a kind of preparation method of 2- aminothiophene -3,4- dicarboxylic acid derivatives, it is characterized in that: the following steps are included:
(1) by pyruvate, cyanoacetate, sulphur powder is reacted in the presence of alkali and solvent, obtains reaction solution；
(2) obtained reaction solution is diluted with ethyl acetate, successively uses aqueous citric acid solution, sodium-chloride water solution, water
Washing obtains 2- aminothiophene -3,4- dicarboxylic acid derivatives crude product solution；
(3) obtained 2- aminothiophene -3,4- dicarboxylic acid derivatives crude product solution is cooled to 0~-20 DEG C, starts to be passed through
Dry hydrogen chloride gas, until solid is all precipitated；
(4) filter cake being obtained by filtration washed once with 0~-20 DEG C of ethyl acetate, with saturated sodium bicarbonate tune pH to 7-8；
(5) liquid separation, collects organic phase, and organic phase is washed to obtain 2- aminothiophene -3,4- dicarboxylic acid derivatives sterling with aqueous solution
Solution；
(6) it removes ethyl acetate and obtains 2- aminothiophene -3,4- dicarboxylic acid derivatives sterling；Reaction equation is as follows:
Wherein: R1、R2It is one of hydrogen atom, methyl, ethyl, n-propyl, isopropyl or tert-butyl, wherein R1With R2It can phase
It is same or different.
2. a kind of preparation method of 2- aminothiophene -3,4- dicarboxylic acid derivatives according to claim 1, it is characterized in that:
Alkali used in step (1) is selected from following one or several kinds: sodium carbonate, potassium carbonate, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, uncle
Sodium butoxide, sodium hydroxide, triethylamine, diethylamine, ammonium hydroxide, diisopropylamine or ethanol amine；Solvent used is selected from DMF, dioxy
One of six rings, tetrahydrofuran, normal propyl alcohol, isopropanol, the tert-butyl alcohol, ethyl alcohol, methanol or water are several.
3. a kind of preparation method of 2- aminothiophene -3,4- dicarboxylic acid derivatives according to claim 2, it is characterized in that:
Alkali used is triethylamine；Solvent used is DMF.
4. a kind of preparation method of 2- aminothiophene -3,4- dicarboxylic acid derivatives according to claim 1, it is characterized in that:
Pyruvate, cyanoacetate, sulphur powder molar ratio=1:1.05:1.2；Range of reaction temperature is -20~70 DEG C.
5. a kind of preparation method of 2- aminothiophene -3,4- dicarboxylic acid derivatives according to claim 1, it is characterized in that:
Aqueous citric acid solution mass percentage concentration is 10%, and sodium-chloride water solution mass percentage concentration is 10%.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113735820A (en) * | 2021-09-16 | 2021-12-03 | 苏州求索生物科技有限公司 | Preparation process of 2, 5-thiophenedicarboxylic acid |
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2019
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113735820A (en) * | 2021-09-16 | 2021-12-03 | 苏州求索生物科技有限公司 | Preparation process of 2, 5-thiophenedicarboxylic acid |
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