CN108840854B - Method for synthesizing 5-chlorothiophene-2-carboxylic acid by one-pot method - Google Patents
Method for synthesizing 5-chlorothiophene-2-carboxylic acid by one-pot method Download PDFInfo
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- CN108840854B CN108840854B CN201811089265.8A CN201811089265A CN108840854B CN 108840854 B CN108840854 B CN 108840854B CN 201811089265 A CN201811089265 A CN 201811089265A CN 108840854 B CN108840854 B CN 108840854B
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- thiophenecarboxaldehyde
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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 invention relates to a method for synthesizing 5-chlorothiophene-2-carboxylic acid by a one-pot method, wherein a chlorinated reagent is introduced or added into 2-thiophenecarboxaldehyde for heat preservation reaction, and an intermediate 5-chloro-2-thiophenecarboxaldehyde is obtained after the reaction is finished and is directly used for the next reaction without separation; slowly dripping the intermediate 5-chloro-2-thiophenecarboxaldehyde into precooled liquid alkali, controlling the reaction temperature not to exceed 30 ℃, cooling after dripping, slowly introducing chlorine, carrying out heat preservation reaction after introducing, cooling to 5 ℃ after the control reaction, adding sodium sulfite for quenching, adding a solvent for extraction and impurity removal, adjusting the pH of a water phase by using concentrated hydrochloric acid, carrying out suction filtration, recrystallizing a filter cake, and drying to obtain the target compound. The invention solves the defects of high price of raw materials, complex operation and more three wastes in the prior art, and provides a method for synthesizing 5-chlorothiophene-2-carboxylic acid, which is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing 5-chlorothiophene-2-carboxylic acid by a one-pot method.
Background
Rivaroxaban is a novel anticoagulant with high efficiency developed by Bayer and Qiangsheng. It can inhibit Xa factor in free or combined state directly with high selectivity to produce anticoagulation effect, and has the features of high bioavailability, wide disease treating spectrum, stable dose-effect relationship, convenient taking and low bleeding risk.
5-chlorothiophene-2-carboxylic acid is an important intermediate for synthesizing rivaroxaban, and a preparation method thereof is reported in documents at present and specifically comprises the following steps:
(1) preparation method using 2-chlorothiophene as raw material
The literature reports a synthesis method of 5-chlorothiophene-2-carboxylic acid: lithium Diisopropylamide (LDA) is used as a strong base, anhydrous tetrahydrofuran is used as a solvent, and gas carbon dioxide is introduced at a low temperature for carbonyl insertion to obtain the product. The route relates to anhydrous and anaerobic operation, has large requirements on equipment, wherein LDA is inflammable and has large operation risk; tetrahydrofuran needs to be subjected to anhydrous treatment before use, peroxide is easily generated after long storage time, and great potential safety hazard exists; in addition, the industrial production of 2-chlorothiophene is limited by a plurality of factors such as high price, low reaction yield and the like [ RSC Advance, 2014, vol.4, # 26, p.13430-13433 ].
Patent CN106146457 discloses: taking 2-chlorothiophene as an initial raw material, carrying out Friedel-crafts acylation with trichloroacetyl chloride under the action of aluminum trichloride to generate 2-trichloroacetyl-5-chlorothiophene, and then carrying out liquid alkali hydrolysis to obtain a target product. The route generates more three wastes in the treatment process, and the raw material trichloroacetyl chloride has higher price and also causes limitation to the industrial production.
(2) Preparation method using 2-chloro-5-bromothiophene as raw material
Patent CN106518840 discloses: reacting 5-chloro-2-bromothiophene with magnesium to generate a Grignard reagent, introducing carbon dioxide for inserting carbonyl, and performing acid-base treatment to obtain a product. The same problems are that the price of the raw materials is high, and the preparation of the Grignard reagent does not need to be operated without water, which is not beneficial to industrial production.
(3) Preparation method of 5-chloro-2-acetylthiophene as raw material
The literature reports that: 5-chloro-2-acetylthiophene is used as a raw material and is oxidized by a sodium chlorite and potassium dihydrogen phosphate system to obtain a target compound. The raw material 5-chloro-2-acetylthiophene required by this route is difficult to prepare, relatively expensive, and the oxidation system has a large amount of waste water and chlorine gas is generated to affect the process safety [ Journal of American Chemical Society,1947, vol.69, p.3096 ].
For review, the following: in the existing route, 2-chlorothiophene is mostly used as a raw material, and because the production of isomers and polychlorinated byproducts is difficult to avoid in the production process of 2-chlorothiophene, the next acylation or carbonyl insertion reaction is carried out to produce corresponding impurities, so that the separation and purification of products are difficult; on the other hand, the content of the 2-chlorothiophene needs to be increased to control other impurities within 0.2 percent, and the rectification operation is also needed, so that the recovery rate is low and the cost is very high; other oxidation processes also have the problems of difficult three-waste treatment, high process risk, low yield and the like.
Disclosure of Invention
The invention aims to solve the defects of high raw material price, complex operation and more three wastes in the prior art and provides a method for synthesizing 5-chlorothiophene-2-carboxylic acid, which is suitable for industrial production.
The invention adopts the technical scheme for solving the technical problems that:
2-thiophenecarboxaldehyde is used as an initial raw material, and a target compound is prepared through two steps of chlorination and oxidation in one pot.
The method comprises the following processes:
introducing or adding chlorine into the 2-thiophenecarboxaldehyde (I), preserving heat for reaction, obtaining an intermediate 5-chloro-2-thiophenecarboxaldehyde (II) after the reaction is finished, and directly using the intermediate in the next reaction without separation.
Slowly dropping the II into a pre-cooled sodium hydroxide solution (liquid caustic soda), controlling the reaction temperature not to exceed 30 ℃, cooling after the dropping is finished, slowly introducing chlorine, carrying out heat preservation reaction after the reaction is finished, cooling to 5 ℃ after the control reaction is finished, adding sodium sulfite for quenching, adding a solvent for extraction and impurity removal, adjusting the pH of a water phase by using concentrated hydrochloric acid, carrying out suction filtration, recrystallizing a filter cake, and drying to obtain the target compound.
In the preparation of the intermediate II, the molar ratio of the chlorine gas to the raw material I is 4: 1-0.9: 1, and preferably 1.5: 1-1.05: 1. The temperature of the heat preservation reaction is-10 to 30 ℃, and preferably-5 to 25 ℃. The heat preservation time is 1-20 hours, preferably 1-3 hours.
In the preparation of the target compound III, the molar ratio of the liquid alkali to the intermediate II is 4: 1-1: 1, preferably 3.5: 1-2.2: 1. The mol ratio of the chlorine to the intermediate II is 3: 1-0.9: 1, preferably 1.5: 0.95: 1.
In the above production of the objective compound III, the organic solvent for impurity removal to be added is selected from chloroform, dichloromethane, dichloroethane, isopropyl acetate, ethyl acetate, toluene, chlorobenzene, and xylene, preferably dichloromethane and isopropyl acetate. In the preparation of the target compound III, the temperature of the liquid alkali when the liquid alkali is dropped in the II is selected from-5 to 40 ℃, and preferably 15 to 30 ℃. The reaction temperature is 10-60 ℃ after chlorine gas is introduced, and the preferable temperature is 15-30 ℃. The pH is adjusted to 1 to 6, preferably 1 to 2. The ratio of ethanol to water in the crystallization solvent is 10:1 to 2:1, preferably 5:1 to 2: 1.
The invention has the beneficial effects that: firstly, 2-thiophenecarboxaldehyde with low price is adopted as a raw material to replace 2-chlorothiophene in the mainstream process, so that the production cost is greatly reduced; secondly, the intermediate 5-chloro-2-thiophenecarboxaldehyde (II) is directly used for the next step after being prepared, no purification is needed, the 2-thiophenecarboxaldehyde in the first step can be used as a solvent, no additional solvent is needed, and the productivity is improved to a great extent; and thirdly, the oxidation reaction adopts in-situ preparation of sodium hypochlorite as an oxidant, so that the amount of wastewater is greatly reduced. By combining the factors, the invention has good prospect for industrial application.
Detailed Description
Example 1:
adding 2.8kg (25mol) of 2-thiophenecarboxaldehyde into a 10L round-bottom four-mouth bottle, cooling to-5 ℃ under mechanical stirring, slowly introducing 1.8kg (25mol) of chlorine, keeping the internal temperature at-5-0 ℃, introducing chlorine for about 3 hours, keeping the internal temperature at-5-0 ℃ after chlorine introduction is finished, continuing to react for 2 hours, wherein TLC shows that the raw materials are completely reacted, and GC shows that 85% of the target intermediate 5-chloro-2-thiophenecarboxaldehyde is obtained.
Slowly dropping the reaction solution into 11kg (55mol) of 20% sodium hydroxide solution at the temperature of 5 ℃ below zero at the internal temperature of-5-0 ℃, controlling the dropping time to be 2 hours, controlling the temperature to be 15-30 ℃, slowly introducing 1.8kg (25mol) of chlorine after the dropping is finished, controlling the temperature to be 15-30 ℃, introducing chlorine for 4 hours, keeping the internal temperature to be 15-30 ℃ after the chlorine introduction is finished, continuing to react for 4 hours, TLC shows that the raw materials disappear, and HPLC shows that the purity of the target product 5-chlorothiophene-2-carboxylic acid is 92%. Stopping the reaction, cooling to 5-10 ℃, adding 10% sodium sulfite aqueous solution to quench until the color of the potassium iodide starch test paper does not change, adding 5kg of dichloromethane, stirring for 30 minutes, standing, separating, barreling the obtained organic layer for reuse, adding 3.65kg (30mol) of 30% hydrochloric acid into the water layer, adjusting the pH value to 1-2, separating out a large amount of white solid, performing suction filtration, keeping the wet weight of the filter cake at 3.6kg and the liquid phase purity at 96%, transferring the filter cake into a 20L round-bottom four-mouth bottle, adding 10.8kg of ethanol and 3.6kg of water, heating to reflux, fully dissolving the system, continuously preserving the temperature for 1 hour, naturally cooling to 30 ℃, continuously cooling to 10 ℃, performing suction filtration, leaching the filter cake once by using 500g of ethanol/water (ethanol: water: 3:1), and performing reduced pressure drying to obtain 3.1kg of a target product 5-chlorothiophene-2-carboxylic acid and the liquid phase.
In addition to the above embodiments, the present invention may have other embodiments. All technical solutions formed by adopting equivalent substitutions or equivalent transformations fall within the protection scope of the claims of the present invention.
Claims (5)
1. A method for synthesizing 5-chlorothiophene-2-carboxylic acid by a one-pot method comprises the following steps:
1) introducing or adding chlorine into 2-thiophenecarboxaldehyde, carrying out heat preservation reaction, obtaining an intermediate 5-chloro-2-thiophenecarboxaldehyde after the reaction is finished, and directly using the intermediate in the next reaction without separation;
2) slowly dripping the intermediate 5-chloro-2-thiophenecarboxaldehyde into a precooled sodium hydroxide solution, controlling the reaction temperature not to exceed 30 ℃, cooling after dripping is finished, slowly introducing chlorine, carrying out heat preservation reaction after introduction is finished, cooling to 5 ℃ after the control reaction is finished, adding sodium sulfite for quenching, adding a solvent for extraction and impurity removal, adjusting the pH of a water phase by using concentrated hydrochloric acid, carrying out suction filtration, recrystallizing a filter cake, and drying to obtain the target compound.
2. The one-pot method for synthesizing 5-chlorothiophene-2-carboxylic acid according to claim 1, which comprises: in the step 1), the heat preservation reaction temperature is-10-30 ℃, and the heat preservation time is 1-20 hours.
3. The one-pot method for synthesizing 5-chlorothiophene-2-carboxylic acid according to claim 1, which comprises: the solvent for removing impurities is selected from chloroform, dichloromethane, dichloroethane, isopropyl acetate, ethyl acetate, toluene, chlorobenzene, and xylene.
4. The one-pot method for synthesizing 5-chlorothiophene-2-carboxylic acid according to claim 1, which comprises: and 2) dripping 5-chloro-2-thiophenecarboxaldehyde into the sodium hydroxide solution in the step 2), wherein the temperature of the sodium hydroxide solution is selected from-5 to 40 ℃, the reaction temperature is selected from 10 to 60 ℃ after chlorine gas is introduced, and the pH is adjusted to be 1 to 6.
5. The one-pot method for synthesizing 5-chlorothiophene-2-carboxylic acid according to claim 1, which comprises: the molar ratio of the chlorine gas to the 2-thiophenecarboxaldehyde is 4: 1-0.9: 1, the molar ratio of the sodium hydroxide solution to the 5-chloro-2-thiophenecarboxaldehyde is 4: 1-1: 1, and the molar ratio of the chlorine gas to the 5-chloro-2-thiophenecarboxaldehyde is 3: 1-0.9: 1.
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| CN110317189B (en) * | 2019-07-19 | 2020-07-28 | 安徽中羰碳一工业技术有限责任公司 | Method for synthesizing 5-chlorothiophene-2-formic acid by taking thiophene-2-formic acid as raw material |
| CN111072628A (en) * | 2019-12-30 | 2020-04-28 | 四川伊诺达博医药科技有限公司 | Method for synthesizing 2-acetyl-4-chlorothiophene |
| CN115403555A (en) * | 2021-05-26 | 2022-11-29 | 上海茂晟康慧科技有限公司 | Synthetic method of rivaroxaban intermediate 5-chlorothiophene-2-carboxylic acid |
| CN115557928B (en) * | 2022-10-25 | 2024-03-19 | 浙江燎原药业有限公司 | Synthesis method of 2-chlorothiophene-5-formic acid |
Citations (3)
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| JP2009221109A (en) * | 2008-03-13 | 2009-10-01 | Konica Minolta Holdings Inc | Method for producing heterocyclic 5-membered ring aldehyde compound |
| CN102993164A (en) * | 2012-11-19 | 2013-03-27 | 连云港宏业化工有限公司 | Preparation method for 2-chlorine-5-thiophene formic acid |
| CN103232430A (en) * | 2013-04-30 | 2013-08-07 | 威海迪素制药有限公司 | Preparation method of rivaroxaban intermediate 5-chlorothiophene-2-carboxylic acid |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009221109A (en) * | 2008-03-13 | 2009-10-01 | Konica Minolta Holdings Inc | Method for producing heterocyclic 5-membered ring aldehyde compound |
| CN102993164A (en) * | 2012-11-19 | 2013-03-27 | 连云港宏业化工有限公司 | Preparation method for 2-chlorine-5-thiophene formic acid |
| CN103232430A (en) * | 2013-04-30 | 2013-08-07 | 威海迪素制药有限公司 | Preparation method of rivaroxaban intermediate 5-chlorothiophene-2-carboxylic acid |
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