CN109422720B - Preparation method of low-cost and high-purity 5-chlorothiophene-2-formyl chloride - Google Patents
Preparation method of low-cost and high-purity 5-chlorothiophene-2-formyl chloride Download PDFInfo
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Abstract
The invention relates to a preparation method of low-cost and high-purity 5-chlorothiophene-2-formyl chloride. The method comprises the steps of utilizing 2-chlorothiophene and a formylation reagent to react to generate 5-chlorothiophene-2-formaldehyde, oxidizing the 5-chlorothiophene-2-formaldehyde by an oxidant to prepare 5-chlorothiophene-2-formic acid, and then carrying out acyl chlorination reaction on the 5-chlorothiophene-2-formic acid and an acyl chlorination reagent to generate 5-chlorothiophene-2-formyl chloride. The 5-chlorothiophene-2-formyl chloride can be used as a key intermediate for preparing rivaroxaban. The raw materials used in the invention are cheap and easily available, the process route is simple, and the raw material cost is low; the method has the advantages of small wastewater discharge amount, low salt content, environmental protection, high reaction selectivity, high purity of the obtained product 5-chlorothiophene-2-formyl chloride and contribution to the industrial production of high-purity rivaroxaban.
Description
Technical Field
The invention relates to a synthetic method of a thiophene derivative, which can be used for preparing rivaroxaban and belongs to the field of pharmaceutical biochemical engineering.
Background
Rivaroxaban, known as Rivaroxaban in English, is a novel oral anticoagulant drug, has long curative effect through oral absorption, is used for preventing and treating venous thrombosis, has wide treatment range and does not need conventional monitoring of blood coagulation function. The first direct factor Xa inhibitor developed worldwide for bayer was approved by the U.S. Food and Drug Administration (FDA) for marketing in 2011. The preparation is mainly used for preventing the formation of deep vein thrombosis and pulmonary thrombosis of patients after hip joint and knee joint replacement in clinic, and can also prevent cerebral apoplexy and non-central nervous system embolism of patients with non-valvular atrial fibrillation, and reduce the recurrence risk of coronary artery syndrome. Its market sales of 1.4, 6.5, 21.1, 37.5, 43.6, 55.6 billion dollars from 2011 to 2016, respectively, and its rapidly increasing sales and superior performance would make it a new milestone in the development history of cardiovascular drugs.
Rivaroxaban (i) has the following structural formula:
wherein the 5-chlorothiophene-2-formyl chloride (II) is a key intermediate for synthesizing rivaroxaban, and the structural formula is as follows:
the main synthetic route of 5-chlorothiophene-2-carbonyl chloride is as follows:
the Journal of the American Chemical Society 1947,69,3096 uses 2-acetyl-5-chlorothiophene as a raw material, prepares 2-trichloroacetyl-5-chlorothiophene by chlorination with sodium hypochlorite at a high concentration, and at the same time, decomposes under alkaline conditions to obtain sodium 5-chlorothiophene-2-carboxylate, which is acidified to obtain 5-chlorothiophene-2-carboxylic acid, and prepares 5-chloro-thiophene-2-carbonyl chloride by acid chlorination, as described in the following synthetic scheme 1:
although the raw materials used in the method are cheap, the raw material 2-acetyl-5-chlorothiophene contains 4-acetyl-2-chlorothiophene and 3-acetyl-2-chlorothiophene isomers, the isomers have similar properties to the main raw material and are difficult to separate completely, the content is generally 0.1 percent or even higher, 2-chlorothiophene-4-formyl chloride and 2-chlorothiophene-3-formyl chloride are generated after the same reaction as the main raw material, and the content of the obtained rivaroxaban impurities is high finally. Meanwhile, the method uses sodium hypochlorite, so that the process waste water amount is large, and the method is not beneficial to environmental protection.
Literature RSC Advances 2014,4(26),13430-13433 uses 2-chlorothiophene as a raw material, obtains 5-chlorothiophene-2-lithium formate through metal lithiation and carbon dioxide reaction, obtains 5-chlorothiophene-2-formic acid after acidification, prepares 5-chlorothiophene-2-formyl chloride through acyl chlorination, and is described as a synthetic route 2 as follows:
although the product obtained by the method has high purity, LDA (lithium diisopropylamide tetrahydrofuran solution) is used in the metallization process of the route, the cost is high, anhydrous and oxygen-free operation is required, the potential safety hazard is high, and the method is not beneficial to cost reduction and industrial production.
Chinese patent document CN106146457A describes the following synthetic route 3, in which 2-chlorothiophene is used as a raw material, and trichloroacetyl chloride is subjected to friedel-crafts acylation reaction to prepare 2-trichloroacetyl-5-chlorothiophene, then decomposed and acidified under alkaline conditions to obtain 5-chlorothiophene-2-carboxylic acid, and then subjected to acyl chlorination to prepare 5-chlorothiophene-2-formyl chloride:
in the route, trichloroacetyl chloride is utilized to carry out Friedel-crafts acylation reaction, the selectivity is poor, 3-trichloroacetyl-5-chlorothiophene, 3-trichloroacetyl-2-chlorothiophene isomers, dechlorination byproducts and byproducts of chlorine atom position replacement are generated, the purification is difficult, the obtained 5-chlorothiophene-2-formyl chloride has more impurities, and finally impurities (such as the following impurities) similar to the structure of rivaroxaban are generated, and the purification is difficult, so that the preparation of high-purity rivaroxaban is not facilitated.
In conclusion, the safe, environment-friendly, low-cost and high-purity production method of the 5-chlorothiophene-2-formyl chloride is established, and has important significance for reducing the cost and improving the purity of rivaroxaban. The invention is particularly proposed based on the idea that the quality of the API is derived from the design.
Disclosure of Invention
Aiming at the defects of the prior art, in particular to the defects that the prior preparation method of 5-chlorothiophene-2-formyl chloride is not beneficial to environmental protection, is easy to generate impurities, has complex and strict preparation conditions and higher cost and the like, the invention provides the preparation method of the 5-chlorothiophene-2-formyl chloride with low cost and high purity.
The technical scheme of the invention is as follows:
a preparation method of 5-chlorothiophene-2-formyl chloride with low cost and high purity comprises the following steps:
(1) reacting 2-chlorothiophene (III) with a formylation reagent to generate 5-chlorothiophene-2-formaldehyde (IV);
(2) carrying out oxidation reaction on the 5-chlorothiophene-2-formaldehyde (IV) and an oxidant to generate 5-chlorothiophene-2-formic acid (V);
(3) performing acyl chlorination reaction on the 5-chlorothiophene-2-formic acid (V) and an acyl chlorination reagent to generate 5-chloro-thiophene-2-formyl chloride (II);
according to the present invention, it is preferred that the formylation reagent in step (1) is phosphorus oxychloride, thionyl chloride, triphosgene or diphosphine; further preferably, the formylation reagent is dissolved in N, N-Dimethylformamide (DMF) and used;
preferably, the molar ratio of the 2-chlorothiophene (III) to the formylating agent in step (1) is 2-chlorothiophene: 1, phosphorus oxychloride: (1.0-2.0), or 2-chlorothiophene: thionyl chloride is 1: (1.0-2.0), or 2-chlorothiophene: triphosgene ═ 1: (0.33-1.0), or 2-chlorothiophene: 1 of diphosphine: (0.5-1.0); further preferably, the molar ratio of 2-chlorothiophene (iii) to DMF is 1: (1.0-6.0);
preferably, the temperature of the formylation reaction in the step (1) is 30-120 ℃, and the reaction is carried out for 2-10 hours; further preferably, the reaction temperature is 40-100 ℃, and the reaction is carried out for 3-5 hours;
preferably, when the formylation reagent is phosphorus oxychloride, the formylation reaction temperature is 90-100 ℃; when the formylation reagent is thionyl chloride, the formylation reaction temperature is 50-60 ℃; when the formylation reagent is triphosgene, the formylation reaction temperature is 40-45 ℃.
According to the present invention, it is preferable that the step (2) oxidizes 5-chlorothiophene-2-carbaldehyde (IV) in a solvent using an oxidizing agent to produce 5-chlorothiophene-2-carboxylic acid (V);
preferably, the oxidant is hydrogen peroxide, tert-butyl hydroperoxide or peracetic acid, and the molar ratio of the oxidant to the 5-chlorothiophene-2-formaldehyde (IV) is (1.0-1.5): 1;
preferably, the solvent is dichloromethane, 1, 2-dichloroethane, chloroform or any mixture thereof, and the mass ratio of the total mass of the solvent to the 5-chlorothiophene-2-formaldehyde (IV) is (4.0-10.0): 1;
preferably, the oxidation reaction temperature in the step (2) is 0-60 ℃, and the reaction time is 1-10 hours; further preferably, the reaction temperature is 20 to 40 ℃ and the reaction time is 3 to 5 hours.
According to the present invention, it is preferred that step (3) is performed by using an acylchlorinating agent in a solvent, and reacting 5-chlorothiophene-2-carboxylic acid (V) through acylchlorination to produce 5-chloro-thiophene-2-carboxylic acid chloride (II);
preferably, the acyl chlorination reagent is thionyl chloride, triphosgene or diphosphine; the molar ratio of the 5-chlorothiophene-2-carboxylic acid (V) to the acylchlorinating agent is 5-chlorothiophene-2-carboxylic acid: thionyl chloride is 1: (1.0-2.0), or 5-chlorothiophene-2-carboxylic acid: triphosgene ═ 1: (0.33-1.0), or 5-chlorothiophene-2-carboxylic acid: 1 of diphosphine: (0.5-1.0);
preferably, the solvent is dichloromethane, 1, 2-dichloroethane, chloroform or any mixture thereof, and the mass ratio of the total mass of the solvent to the 5-chlorothiophene-2-formaldehyde (IV) is (4.0-10.0): 1;
preferably, the temperature of the acyl chlorination reaction in the step (3) is 20-80 ℃, the reaction time is 1-12 hours, and the reaction temperature is 30-70 ℃ for 2-6 hours.
The process of the present invention is depicted as the following reaction scheme (scheme 4):
the invention has the technical characteristics and beneficial effects that:
1. the invention utilizes 2-chlorothiophene and formylation reagent to react to generate 5-chlorothiophene-2-formaldehyde, the 5-chlorothiophene-2-formic acid is prepared by oxidizing with oxidant, and then the 5-chlorothiophene-2-formyl chloride is generated by acyl chlorination reaction with acyl chlorination reagent, and the 5-chlorothiophene-2-formyl chloride is a key intermediate for preparing rivaroxaban.
2. The method has the advantages of cheap and easily obtained raw materials, simple process route, small wastewater discharge amount, low salt content and contribution to environmental protection.
3. In the process of preparing 5-chlorothiophene-2-formaldehyde by reacting 2-chlorothiophene with a formylation reagent, the formylation reaction temperature is in a proper range, so that the 5-chlorothiophene-2-formaldehyde has higher yield which is more than 95 percent; the total yield of the final product in the whole reaction process can reach more than 92 percent.
4. The selectivity of each step of the method is very high, and the selectivity of GC or HPLC analysis is over 99.9 percent; the obtained 5-chlorothiophene-2-formaldehyde does not contain isomerides, the GC purity of the 5-chlorothiophene-2-formaldehyde is more than 99.97 percent, the preparation of high-purity 5-chlorothiophene-2-formyl chloride is guaranteed, and the industrial production of high-purity rivaroxaban is facilitated.
Detailed Description
The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.
The raw materials and reagents used in the examples are all commercially available products. In the examples, "%" is a mass percentage unless otherwise specified.
Example 1: preparation of 5-chlorothiophene-2-carbaldehyde (IV)
200 g of N, N-Dimethylformamide (DMF) and 118.5 g (1.0 mol) of 2-chlorothiophene are added into a 1L dry four-mouth bottle which is connected with a stirring device, a thermometer, a condensation tube and a constant pressure dropping funnel, heating is carried out, the internal temperature is kept between 40 and 60 ℃, 169 g (1.1 mol) of phosphorus oxychloride is slowly dropped into the bottle through the constant pressure dropping funnel, and the mixture is stirred for 2 hours at the temperature of 95 to 100 ℃. Cooling to 20 ℃, pouring the reaction liquid into a beaker filled with 400 g of crushed ice and 400 g of water, neutralizing the reaction liquid with 30% sodium hydroxide solution until the pH value is 6-7, separating an oil layer, extracting a water layer with dichloromethane for 3 times, using 300 g of dichloromethane each time, combining a dichloromethane layer and the separated oil layer, washing an organic phase with 50 g of water once, distilling the organic phase to recover dichloromethane, and then carrying out reduced pressure distillation to obtain 141.5 g of 5-chlorothiophene-2-formaldehyde, wherein the yield is 96.6% and the GC purity is 99.97%.
The nuclear magnetic resonance hydrogen spectrum data of the product 5-chlorothiophene-2-formaldehyde is as follows:
1HNMR(400MHz,CDCl3)
δ:7.08,d,1H,7.75,d,1H,10.03,s,1H
example 2: preparation of 5-chlorothiophene-2-carbaldehyde (IV)
200 g of N, N-Dimethylformamide (DMF) and 118.5 g (1.0 mol) of 2-chlorothiophene are added into a 1L dry four-mouth bottle which is connected with a stirring device, a thermometer, a condensation tube, an alkali liquor absorption system and a constant pressure dropping funnel, heating is carried out, the internal temperature is kept between 40 ℃ and 50 ℃, 130 g (1.1 mol) of thionyl chloride is slowly dropped into the bottle through the constant pressure dropping funnel, and the bottle is stirred for 5 hours at 55 ℃ to 60 ℃ after dropping. Cooling to 20 ℃, pouring the reaction liquid into a beaker filled with 400 g of crushed ice and 400 g of water, neutralizing the reaction liquid with 30% sodium hydroxide solution until the pH value is 6-7, separating an oil layer, extracting a water layer with dichloromethane for 3 times, using 300 g of dichloromethane each time, combining a dichloromethane layer and the separated oil layer, washing an organic phase with 50 g of water once, distilling the organic phase to recover dichloromethane, and then carrying out reduced pressure distillation to obtain 139.2 g of 5-chlorothiophene-2-formaldehyde with the yield of 95.0% and the GC purity of 99.98%.
Example 3: preparation of 5-chlorothiophene-2-carbaldehyde (IV)
Adding 200 g of N, N-Dimethylformamide (DMF) and 118.5 g (1.0 mol) of 2-chlorothiophene into a 1L dry four-mouth bottle connected with a stirring device, a thermometer, a condensation pipe, an alkali liquor absorption system and a constant-pressure dropping funnel, heating, keeping the internal temperature between 35 and 40 ℃, slowly dropping a solution of 108 g (0.36 mol) of triphosgene and 300 g of dichloromethane into the bottle through the constant-pressure dropping funnel, and after the dropping, carrying out reflux stirring for 6 hours. Cooling to 20 ℃, pouring the reaction liquid into a beaker filled with 400 g of crushed ice and 400 g of water, neutralizing the reaction liquid with 30% sodium hydroxide solution until the pH value is 6-7, separating an oil layer, extracting a water layer with dichloromethane for 3 times, using 200 g of dichloromethane each time, combining a dichloromethane layer and the separated oil layer, washing an organic phase with 50 g of water once, distilling the organic phase to recover dichloromethane, and then carrying out reduced pressure distillation to obtain 140.5 g of 5-chlorothiophene-2-formaldehyde with the yield of 95.9% and the GC purity of 99.97%.
Example 4: preparation of 5-chlorothiophene-2-carboxylic acid (V)
200 g of dichloromethane, 29.5 g (0.2 mol) of 5-chlorothiophene-2-formaldehyde and 30 g of 30% hydrogen peroxide are added into a 500 ml four-mouth bottle with a stirring thermometer, and stirred and reacted for 6 hours at 25-30 ℃. The layers were separated, the aqueous layer was extracted 3 times with dichloromethane, 50 g of dichloromethane each time, the dichloromethane layers were combined, the organic phase was washed once with 20 g of 5% aqueous sodium sulfite solution, dichloromethane was recovered by distilling the organic phase, and the residue was recrystallized from petroleum ether to give 30.5 g of white solid 5-chlorothiophene-2-carboxylic acid, yield 93.8%, HPLC purity 99.98%.
The nuclear magnetic resonance hydrogen spectrum data of the product 5-chlorothiophene-2-formic acid are as follows:
1HNMR(400MHz,DMSO)
δ:7.12,d,1H,7.72,d,1H,10.8,s,1H
example 5: preparation of 5-chlorothiophene-2-carboxylic acid (V)
To a 500 ml four-necked flask equipped with a stirrer and a thermometer, 200 g of methylene chloride, 29.5 g (0.2 mol) of 5-chlorothiophene-2-carbaldehyde, and 32.0 g of 70% t-butyl hydroperoxide were added and the reaction was carried out with stirring at 35 to 40 ℃ for 4 hours. 10 g of 5% sodium sulfite aqueous solution was added, layers were separated, the aqueous layer was extracted 3 times with 30 g of dichloromethane each time, the dichloromethane layers were combined, the dichloromethane was recovered by distilling the organic phase, and the residue was recrystallized from petroleum ether to give 31.2 g of white solid 5-chlorothiophene-2-carboxylic acid with a yield of 96.0% and a HPLC purity of 99.98%.
Example 6: preparation of 5-chlorothiophene-2-carbonyl chloride (II)
To a dry 250 ml four-necked flask equipped with a stirrer, a thermometer and an alkali solution absorption system, 100 g of methylene chloride, 16.5 g (0.1 mol) of 5-chlorothiophene-2-carboxylic acid, 1 drop of N, N-dimethylformamide, 15 g of thionyl chloride were added and reacted at 40 ℃ for 4 hours with stirring. The dichloromethane and the excessive thionyl chloride are recovered by distillation, and 18.0 g of colorless liquid 5-chlorothiophene-2-formyl chloride is obtained by reduced pressure distillation (80-90 ℃/5mmHg), the yield is 100.0 percent, and the GC purity is 99.98 percent.
The nuclear magnetic resonance hydrogen spectrum data of the product 5-chlorothiophene-2-formyl chloride is as follows:
1HNMR(400MHz,CDCl3)
δ:7.07,d,1H,7.83,d,1H
the gas chromatographic data of the product 5-chlorothiophene-2-carbonyl chloride are as follows:
GC-MS(EI+m/z)180,182,184。
example 7: preparation of 5-chlorothiophene-2-carbonyl chloride (II)
To a dry 250 ml four-necked flask equipped with a stirrer, a thermometer and an alkali solution absorption system, 100 g of 1, 2-dichloroethane, 16.5 g (0.1 mol) of 5-chlorothiophene-2-carboxylic acid, 1 drop of N, N-dimethylformamide, 12 g of triphosgene were added, and the mixture was reacted at 60 ℃ for 5 hours with stirring. Distilling to recover 1, 2-dichloroethane, and distilling under reduced pressure (80-90 deg.C/5 mmHg) to obtain 18.0 g colorless liquid 5-chlorothiophene-2-formyl chloride, with yield of 100.0% and GC purity of 99.99%.
Comparative example 1: preparation of 5-chlorothiophene-2-carbaldehyde (IV)
200 g of N, N-Dimethylformamide (DMF) and 118.5 g (1.0 mol) of 2-chlorothiophene are added into a 1L dry four-mouth bottle which is connected with a stirring device, a thermometer, a condensation tube and a constant pressure dropping funnel, heating is carried out, the internal temperature is kept between 40 and 50 ℃, 169 g (1.1 mol) of phosphorus oxychloride is slowly dropped from the constant pressure dropping funnel, and stirring is carried out for 8 hours at the temperature of 40 to 50 ℃. Cooling to 20 ℃, pouring the reaction liquid into a beaker filled with 400 g of crushed ice and 400 g of water, neutralizing the reaction liquid with 30% sodium hydroxide solution until the pH value is 6-7, separating an oil layer, extracting a water layer for 3 times by using dichloromethane, using 300 g of dichloromethane each time, combining a dichloromethane layer and the separated oil layer, washing an organic phase once by using 50 g of water, distilling the organic phase to recover dichloromethane and unreacted 2-chlorothiophene, and then distilling under reduced pressure to obtain 38.8 g of 5-chlorothiophene-2-formaldehyde, wherein the yield is 26.5% and the GC purity is 99.96%.
Comparative example 2: preparation of 5-chlorothiophene-2-carbaldehyde (IV)
200 g of N, N-Dimethylformamide (DMF) and 118.5 g (1.0 mol) of 2-chlorothiophene are added into a 1L dry four-mouth bottle which is connected with a stirring device, a thermometer, a condensation pipe, an alkali liquor absorption system and a constant pressure dropping funnel, heating is carried out, the internal temperature is kept between 40 and 50 ℃, 130 g (1.1 mol) of thionyl chloride is slowly dropped into the bottle through the constant pressure dropping funnel, and the bottle is stirred for 5 hours at the temperature of between 40 and 50 ℃ after dropping. Cooling to 20 ℃, pouring the reaction liquid into a beaker filled with 400 g of crushed ice and 400 g of water, neutralizing the reaction liquid with 30% sodium hydroxide solution until the pH value is 6-7, separating an oil layer, extracting a water layer for 3 times by using dichloromethane, using 300 g of dichloromethane each time, combining a dichloromethane layer and the separated oil layer, washing an organic phase once by using 50 g of water, distilling the organic phase to recover dichloromethane and unreacted 2-chlorothiophene, and then distilling under reduced pressure to obtain 74.4 g of 5-chlorothiophene-2-formaldehyde with the yield of 50.8% and the GC purity of 99.99%.
Comparative example 3: preparation of 5-chlorothiophene-2-carbaldehyde (IV)
Adding 200 g of N, N-Dimethylformamide (DMF) and 118.5 g (1.0 mol) of 2-chlorothiophene into a 1L dry four-mouth bottle connected with a stirring device, a thermometer, a condensation pipe, an alkali liquor absorption system and a constant pressure dropping funnel, heating, keeping the internal temperature between 25 and 30 ℃, slowly dropping 108 g (0.36 mol) of triphosgene and 300 g of dichloromethane into the bottle through the constant pressure dropping funnel, and stirring and reacting for 8 hours after dropping. Cooling to 20 ℃, pouring the reaction liquid into a beaker filled with 400 g of crushed ice and 400 g of water, neutralizing the reaction liquid with 30% sodium hydroxide solution until the pH value is 6-7, separating an oil layer, extracting a water layer for 3 times by using dichloromethane, combining a dichloromethane layer and the separated oil layer by using 200 g of dichloromethane each time, washing an organic phase once by using 50 g of water, distilling the organic phase to recover dichloromethane and unreacted 2-chlorothiophene, and then distilling under reduced pressure to obtain 102.6 g of 5-chlorothiophene-2-formaldehyde, wherein the yield is 70.0%, and the GC purity is 99.92%.
As can be seen from the comparison of examples 1-3 and comparative examples 1-3, comparative examples 1-3 have a reaction temperature lower than that of examples 1-3 under the same conditions as the formylation reagents, and as a result, the yield of the product 5-chlorothiophene-2-formaldehyde is much lower than that of examples 1-3, indicating that the invention ensures a high yield of the product 5-chlorothiophene-2-formaldehyde at a proper temperature.
The present invention is not limited to the above-described embodiments.
Claims (1)
1. A preparation method of 5-chlorothiophene-2-formyl chloride with low cost and high purity comprises the following steps:
(1) reacting 2-chlorothiophene (III) with a formylation reagent to generate 5-chlorothiophene-2-formaldehyde (IV);
the formylation reagent is phosphorus oxychloride, thionyl chloride, triphosgene or diphosphine, when the formylation reagent is phosphorus oxychloride,
the formylation reaction temperature is 90-100 ℃; when the formylation reagent is thionyl chloride, the formylation reaction temperature is 50-60 ℃; when the formylation reagent is triphosgene, the formylation reaction temperature is 40-45 ℃;
(2) oxidizing 5-chlorothiophene-2-formaldehyde (IV) in a solvent by using an oxidant to generate 5-chlorothiophene-2-formic acid (V), wherein the oxidant is hydrogen peroxide, tert-butyl hydroperoxide or peracetic acid;
the preparation process comprises the following steps:
adding 200 g of dichloromethane, 29.5 g of 5-chlorothiophene-2-formaldehyde, 30 g of 30% hydrogen peroxide into a 500 ml four-mouth bottle connected with a stirring thermometer, and stirring for reacting for 6 hours at 25-30 ℃; layering, extracting the water layer with dichloromethane for 3 times, 50 g of dichloromethane each time, combining dichloromethane layers, washing the organic phase with 20 g of 5% sodium sulfite aqueous solution once, distilling the organic phase to recover dichloromethane, and recrystallizing the remainder with petroleum ether to obtain 30.5 g of white solid 5-chlorothiophene-2-formic acid;
or adding 200 g of dichloromethane, 29.5 g of 5-chlorothiophene-2-formaldehyde and 32.0 g of 70% tert-butyl hydroperoxide into a 500 ml four-mouth bottle connected with a stirring thermometer, and stirring for reaction at 35-40 ℃ for 4 hours; adding 10 g of 5% sodium sulfite aqueous solution, layering, extracting a water layer by using dichloromethane for 3 times, 30 g of dichloromethane each time, combining dichloromethane layers, distilling an organic phase to recover dichloromethane, and recrystallizing residues by using petroleum ether to obtain 31.2 g of white solid 5-chlorothiophene-2-formic acid;
(3) using an acyl chlorination reagent to perform acyl chlorination reaction with 5-chlorothiophene-2-formic acid (V) in a solvent to generate 5-chloro-thiophene-2-formyl chloride (II), wherein the acyl chlorination reagent is thionyl chloride, triphosgene or diphosphonate, and the temperature of the acyl chlorination reaction is 20-80 ℃;
the preparation process comprises the following steps:
adding 100 g of dichloromethane, 16.5 g of 5-chlorothiophene-2-formic acid, 1 drop of N, N-dimethylformamide and 15 g of thionyl chloride into a dry 250 ml four-mouth bottle connected with a stirring system, a thermometer and an alkali liquor absorption system, and stirring at 40 ℃ for reacting for 4 hours; distilling and recovering dichloromethane and excessive thionyl chloride, and distilling at 80-90 ℃/5mmHg under reduced pressure to obtain 18.0 g of colorless liquid 5-chlorothiophene-2-formyl chloride;
or adding 100 g of 1, 2-dichloroethane, 16.5 g of 5-chlorothiophene-2-formic acid, 1 drop of N, N-dimethylformamide and 12 g of triphosgene into a dry 250 ml four-mouth bottle connected with a stirring system, a thermometer and an alkali liquor absorption system, and stirring at 60 ℃ for reacting for 5 hours; distilling to recover 1, 2-dichloroethane, distilling at 80-90 deg.C/5 mmHg under reduced pressure to obtain 18.0 g colorless liquid 5-chlorothiophene-2-formyl chloride;
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