CN115557928B - Synthesis method of 2-chlorothiophene-5-formic acid - Google Patents
Synthesis method of 2-chlorothiophene-5-formic acid Download PDFInfo
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- CN115557928B CN115557928B CN202211308456.5A CN202211308456A CN115557928B CN 115557928 B CN115557928 B CN 115557928B CN 202211308456 A CN202211308456 A CN 202211308456A CN 115557928 B CN115557928 B CN 115557928B
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- chlorothiophene
- thiophene
- ethyl formate
- carboxylic acid
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- QZLSBOVWPHXCLT-UHFFFAOYSA-N 5-chlorothiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Cl)S1 QZLSBOVWPHXCLT-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 238000001308 synthesis method Methods 0.000 title claims abstract description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 25
- HGAPCFNXSLPISY-UHFFFAOYSA-N S1C=CC=C1.C(=O)OCC Chemical compound S1C=CC=C1.C(=O)OCC HGAPCFNXSLPISY-UHFFFAOYSA-N 0.000 claims abstract description 23
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 claims abstract description 17
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims abstract description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000000126 substance Substances 0.000 claims abstract description 9
- 238000005886 esterification reaction Methods 0.000 claims abstract description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- BMOKMXXTOZFEIZ-UHFFFAOYSA-N ethyl 5-chlorothiophene-2-carboxylate Chemical compound CCOC(=O)C1=CC=C(Cl)S1 BMOKMXXTOZFEIZ-UHFFFAOYSA-N 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 239000012065 filter cake Substances 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 8
- JZGZKRJVTIRPOK-UHFFFAOYSA-N ethyl thiophene-2-carboxylate Chemical compound CCOC(=O)C1=CC=CS1 JZGZKRJVTIRPOK-UHFFFAOYSA-N 0.000 claims 2
- 239000002994 raw material Substances 0.000 abstract description 8
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 3
- 238000005660 chlorination reaction Methods 0.000 abstract description 2
- 230000032050 esterification Effects 0.000 abstract description 2
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 6
- GSFNQBFZFXUTBN-UHFFFAOYSA-N 2-chlorothiophene Chemical compound ClC1=CC=CS1 GSFNQBFZFXUTBN-UHFFFAOYSA-N 0.000 description 5
- 239000002351 wastewater Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 description 3
- 229960001148 rivaroxaban Drugs 0.000 description 3
- 229950009390 symclosene Drugs 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 108010074860 Factor Xa Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- JWQMRBBWZUKWFJ-UHFFFAOYSA-N 4-chlorothiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC(Cl)=CS1 JWQMRBBWZUKWFJ-UHFFFAOYSA-N 0.000 description 1
- VWYFITBWBRVBSW-UHFFFAOYSA-N 5-chlorothiophene-2-carbaldehyde Chemical compound ClC1=CC=C(C=O)S1 VWYFITBWBRVBSW-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002485 combustion reaction Methods 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- QEHKBHWEUPXBCW-UHFFFAOYSA-N nitrogen trichloride Chemical compound ClN(Cl)Cl QEHKBHWEUPXBCW-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000010405 reoxidation reaction Methods 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Abstract
The invention discloses a synthesis method of 2-chlorothiophene-5-formic acid, which comprises the following steps: under the action of concentrated sulfuric acid, thiophene-2-formic acid and ethanol undergo esterification reaction to generate thiophene-2-ethyl formate; chloridizing thiophene-2-ethyl formate with sulfonyl chloride in a methylene dichloride and N, N-dimethylformamide system to generate 2-chlorothiophene-5-ethyl formate; carrying out hydrolysis reaction on the 2-chlorothiophene-5-ethyl formate under the action of alkaline substances to generate 2-chlorothiophene-5-formic acid; according to the method, thiophene-2-formic acid is used as a raw material, and is subjected to esterification, chlorination and hydrolysis to obtain the 2-chlorothiophene-5-formic acid, the method is novel, the operation is simple, raw materials and auxiliary materials are cheap and easy to obtain, the reaction is mild, the selectivity is high, the product yield and purity are high, the amount of three wastes is small, the method is more environment-friendly, and the method is suitable for large-scale production;
Description
Technical Field
The invention relates to a synthesis method of 2-chlorothiophene-5-formic acid, belonging to the technical field of drug synthesis.
Background
2-chlorothiophene-5-carboxylic acid is an important intermediate of rivaroxaban as an anticoagulant. Rivaroxaban is an oral factor Xa direct inhibitor jointly developed by Bayer and Qiangsheng, has high selective and competitive inhibition effect on free and combined factor Xa, clinical experiments show that rivaroxaban has less interaction with other medicines due to the pharmaceutical parameters and pharmacokinetics, is less influenced by factors such as age, sex and the like of a person to be administrated, and is an excellent oral anticoagulation medicine.
The synthesis method of 2-chlorothiophene-5-formic acid is different from the selection of the starting materials, and mainly adopts 2-chlorothiophene or thiophene-2-formic acid as the synthesis method of the starting materials.
The synthesis method of the 2-chlorothiophene is that 2-chlorothiophene-5-formic acid is prepared by acylation and oxidation. Chinese patent CN109422720A uses 2-chlorothiophene as raw material, formylates to obtain 2-chlorothiophene-5-formaldehyde, and oxidizes to obtain 2-chlorothiophene-5-formic acid, and the main method is that the generated phosphorus wastewater has large treatment capacity and the synthetic route is as follows:
chinese patent CN 102993164A takes 2-chlorothiophene as raw material, 2-chlorothiophene-5-acetyl is obtained by acetylation, 2-chlorothiophene-5-formic acid is obtained by reoxidation, and the main method is that the generated phosphorus wastewater has large treatment capacity and the synthetic route is as follows:
patent document RSC Advances 2014,4 (26), 13430-13433 takes 2-chlorothiophene as raw material, reacts with carbon dioxide, LDA as catalyst, and acidizes to obtain 2-chlorothiophene-5-formic acid, which mainly has harsh reaction conditions, high LDA price and high danger, is not suitable for large-scale production, and has a synthetic route:
chinese patent CN 110317189B uses thiophene-2-formic acid as raw material, and trichloroisocyanuric acid as chlorinating agent to obtain 2-chlorothiophene-5-formic acid. The method has the advantages that the method is simple to operate, the reaction is severe, the feeding speed and the reaction temperature of trichloroisocyanuric acid are required to be strictly controlled, byproducts such as 3-chlorothiophene-5-formic acid and the like are easy to generate, the generated acid wastewater is large in quantity, the residual trichloroisocyanuric acid in the wastewater needs to be paid attention before being discharged into a wastewater tank, nitrogen trichloride is avoided, combustion explosion occurs, and the synthetic route is as follows:
in conclusion, the method which is favorable for environmental protection, low in cost, good in quality, simple to operate and high in safety, can be applied to production amplification and is mainly researched in the synthesis and preparation of the 2-chlorothiophene-5-formic acid is developed.
Disclosure of Invention
The invention provides a novel synthetic method of 2-chlorothiophene-5-formic acid, which adopts thiophene-2-formic acid to be esterified firstly, then reacts with a chloridizing reagent sulfonyl chloride which is cheap and easy to obtain and has mild reaction conditions, and alkaline hydrolysis is carried out to obtain a product.
The technical scheme of the invention is as follows:
the synthesis method of the 2-chlorothiophene-5-formic acid comprises the following steps:
(1) Under the action of concentrated sulfuric acid (98 wt%) thiophene-2-formic acid and ethyl alcohol, the thiophene-2-ethyl formate is produced by esterification reaction;
(2) Chloridizing thiophene-2-ethyl formate with sulfonyl chloride in a methylene dichloride and N, N-dimethylformamide system to generate 2-chlorothiophene-5-ethyl formate;
(3) And (3) carrying out hydrolysis reaction on the 2-chlorothiophene-5-ethyl formate under the action of alkaline substances to generate 2-chlorothiophene-5-formic acid.
Specifically, the operation method of the step (1) is as follows:
mixing thiophene-2-formic acid with ethanol, dropwise adding concentrated sulfuric acid, heating to 75-85 ℃ after the dropwise adding, reacting for 6-10 h, and then performing aftertreatment to obtain thiophene-2-ethyl formate;
the mass ratio of the thiophene-2-formic acid to the ethanol is 1:2-5, preferably 1:3-4;
the mass ratio of the thiophene-2-formic acid to the concentrated sulfuric acid is 1:0.05-0.15, preferably 1:0.08-0.09;
the post-treatment method comprises the following steps: after the reaction is finished, the reaction solution is decompressed and evaporated to dryness, water is added, pH=7-7.5 is adjusted by liquid alkali, methyl tertiary butyl ether is used for extraction, the solvent is evaporated from the extract liquid, and the thiophene-2-ethyl formate is obtained.
Specifically, the operation method of the step (2) is as follows:
mixing thiophene-2-ethyl formate, dichloromethane and N, N-dimethylformamide, heating to 35-39 ℃, dropwise adding sulfonyl chloride, carrying out heat preservation reaction for 12-18 h after the dropwise addition, and then evaporating under reduced pressure to obtain 2-chlorothiophene-5-ethyl formate;
the mass ratio of the thiophene-2-ethyl formate to the dichloromethane to the N, N-dimethylformamide is 25:100-300:0.15-1.15, preferably 25:250-300:0.35-0.75;
the mol ratio of the thiophene-2-ethyl formate to the sulfonyl chloride is 1:1.21-3.58, preferably 1:2.15-3.35.
Specifically, the operation method of the step (3) is as follows:
mixing 2-chlorothiophene-5-ethyl formate with an aqueous solution of an alkaline substance, reacting for 4-10 hours (preferably 4-6 hours) at 30-80 ℃ (preferably 50-80 ℃), then adding active carbon, stirring for 1-2 hours, filtering, cooling the filtrate to room temperature, regulating the pH value to be 0.5-2.5 by using refined hydrochloric acid, cooling to 5-15 ℃, stirring for 2 hours, filtering, and drying a filter cake to obtain 2-chlorothiophene-5-formic acid;
the aqueous solution of the alkaline substance is preferably 15-18 wt% aqueous solution of sodium hydroxide; the mass ratio of the aqueous solution of the alkaline substance to the ethyl 2-chlorothiophene-5-carboxylate is 4-6:1, preferably 5-6:1;
preferably, the mass ratio of the active carbon to the 2-chlorothiophene-5-ethyl formate is 0.03-0.08:1;
the mass ratio of the refined hydrochloric acid to the ethyl 2-chlorothiophene-5-formate is 1.4-2.5:1, preferably 1.6-1.8:1.
The reaction equation of the present invention is as follows:
the innovation of the invention is that: the esterification of thiophene-2-formic acid as raw material can raise the chlorination activity of sulfonyl chloride as chlorinating agent, and then the hydrolysis is carried out to obtain the product, so that the method is a novel synthetic method for preparing 2-chlorothiophene-5-formic acid. The method has the advantages of simple operation, cheap and easily available raw materials and auxiliary materials, high reaction selectivity, high yield, less three wastes, and more environmental protection, and is suitable for large-scale production because the waste gas mainly generated by the three wastes can be absorbed by alkaline water.
Drawings
FIG. 1 shows the nuclear magnetic resonance hydrogen spectrum of 2-chlorothiophene-5-carboxylic acid prepared according to the invention.
FIG. 2 is a nuclear magnetic resonance carbon spectrum of 2-chlorothiophene-5-carboxylic acid prepared according to the invention.
Detailed Description
The present invention is further described below by way of specific examples, but the scope of the present invention is not limited thereto.
Example 1:
preparation of thiophene-2-ethyl formate: adding 30g of thiophene-2-formic acid and 120g of ethanol into a 250ml reaction bottle, stirring and dissolving, dripping 2.55g of concentrated sulfuric acid, heating to 80 ℃ and preserving heat for reaction for 6 hours, concentrating the solvent until no flow, cooling to room temperature, adding water, adjusting pH to 7.5 with 24.2g of liquid alkali, extracting 3 times with 3X 30ml of methyl tertiary butyl ether, and distilling to obtain 34.13g of thiophene-2-ethyl formate, wherein the yield is 89.79%, and the purity is 99.46%. 1 H NMR(500MHz,CDCl 3 ):δ＝7.79(dd,J＝3.7,1.2Hz,1H),7.54(dd,J＝5.0,1.2Hz,1H),7.09(dd,J＝4.9,3.8Hz,1H),4.35(q,J＝7.1Hz,2H),1.37(t,J＝7.1Hz,3H)。
Preparation of 2-chlorothiophene-5-ethyl formate: 25g (0.16 mol) of thiophene-2-ethyl formate, 300ml of dichloromethane and 0.6g of N, N-dimethylformamide are added into a reaction vessel, the temperature is raised to 35 ℃, 54g (0.4 mol) of sulfonyl chloride is added dropwise, the reaction is carried out for 15 hours at the temperature of 35-39 ℃, the solvent is distilled until no flow is generated, and 30.41g of 2-chlorothiophene-5-ethyl formate is obtained, the yield is 99.66%, and the purity is 99.63%. 1 HNMR:δ＝1.36(t,J＝7.3Hz,2H),4.33(q,J＝7.3Hz,3H),6.92(d,J＝4.0Hz,1H),7.58(d,J＝4.0Hz,1H)。
Preparation of 2-chlorothiophene-5-carboxylic acid: adding 135g of 16.7% sodium hydroxide aqueous solution into a reaction vessel of 30g of 2-chlorothiophene-5-ethyl formate, heating to 65-75 ℃, preserving heat and reacting for 4 hours, adding 1g of active carbon, stirring for 1 hour, filtering, cooling the filtrate to room temperature, dropwise adding 42.5g of refined hydrochloric acid to adjust the pH to 0.5, cooling to 5-15 ℃, stirring for 2 hours, filtering, and drying to obtain 21.1g of 2-chlorothiophene-5-formic acid with the purity of 99.87% and the yield of 82.47%. [ M-H ]] - ＝160.7， 1 H NMR(DMSO-d6；δ H Nuclear magnetic resonance hydrogen spectrum (fig. 1):
s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet, dt=doublet, doublet, brs=broad, singlet
13 C NMR(DMSO-d6；δ C =39.90, 39.76,39.62,39.48,39.34,39.20,39.06, ppm), nuclear magnetic resonance carbon spectrum (fig. 2):
example 2:
preparation of thiophene-2-ethyl formate: adding 30g of thiophene-2-formic acid and 120g of ethanol into a 250ml reaction bottle, stirring and dissolving, dripping 2.55g of concentrated sulfuric acid, heating to 80 ℃ and preserving heat for reaction for 6 hours, concentrating the solvent until no flow is generated, cooling to room temperature, adding water, adjusting pH to 7.5 with 24.2g of liquid alkali, extracting 3 times with 3X 30ml of methyl tertiary butyl ether, and distilling to obtain 33.95g of thiophene-2-ethyl formate, wherein the yield is 89.32%, and the purity is 99.52%;
preparation of 2-chlorothiophene-5-ethyl formate: 25g (0.16 mol) of thiophene-2-ethyl formate, 300ml of dichloromethane and 0.6g of N, N-dimethylformamide are added into a reaction vessel, the temperature is raised to 35 ℃, 52g (0.39 mol) of sulfonyl chloride is added dropwise, the reaction is carried out for 15 hours at the temperature of 35-39 ℃, the solvent is distilled until no flow exists, and 30.36g of 2-chlorothiophene-5-ethyl formate is obtained, the yield is 99.5%, and the purity is 99.62%.
Preparation of 2-chlorothiophene-5-carboxylic acid: adding 135g of 16.7% sodium hydroxide aqueous solution into a reaction vessel of 30g of 2-chlorothiophene-5-ethyl formate, heating to 65-75 ℃, preserving heat and reacting for 4 hours, adding 1g of active carbon, stirring for 1 hour, filtering, cooling the filtrate to room temperature, dropwise adding 42.5g of refined hydrochloric acid to adjust the pH to 0.5, cooling to 5-15 ℃, stirring for 2 hours, filtering, and drying to obtain 20.6g of 2-chlorothiophene-5-formic acid with the purity of 99.86% and the yield of 80.51%.
Example 3:
preparation of thiophene-2-ethyl formate: adding 30g of thiophene-2-formic acid and 120g of ethanol into a 250ml reaction bottle, stirring and dissolving, dripping 2.55g of concentrated sulfuric acid, heating to 80 ℃ and preserving heat for reaction for 6 hours, concentrating the solvent until no flow rate exists, cooling to room temperature, adding water, adjusting pH to 7.5 with 24.2g of liquid alkali, extracting 3 times with 3X 30ml of methyl tertiary butyl ether, and distilling to obtain 34.25g of thiophene-2-ethyl formate, wherein the yield is 90.11%, and the purity is 99.49%;
preparation of 2-chlorothiophene-5-ethyl formate: 25g (0.16 mol) of thiophene-2-ethyl formate, 300ml of dichloromethane and 0.6g of N, N-dimethylformamide are added into a reaction vessel, the temperature is raised to 35 ℃, 56g (0.41 mol) of sulfonyl chloride is added dropwise, the reaction is carried out for 15 hours at the temperature of 35-39 ℃, the solvent is distilled until no flow exists, and 30.4g of 2-chlorothiophene-5-ethyl formate is obtained, the yield is 99.63%, and the purity is 99.6%.
Preparation of 2-chlorothiophene-5-carboxylic acid: 135g of 16.7% sodium hydroxide aqueous solution is added into a reaction vessel of 30g of 2-chlorothiophene-5-ethyl formate, the temperature is raised to 65-75 ℃ for reaction for 4 hours at a constant temperature, 1g of active carbon is added, stirring is carried out for 1 hour, filtering is carried out, the filtrate is cooled to room temperature, 42.5g of refined hydrochloric acid is added dropwise for regulating the pH to 0.5, cooling is carried out to 5-15 ℃ for stirring for 2 hours, filtering is carried out, drying is carried out, 20.9g of 2-chlorothiophene-5-formic acid is obtained, the purity is 99.84%, and the yield is 81.69%.
The foregoing describes the embodiments of the present invention in detail, but the description should not be construed as limiting the invention. Modifications and variations in the detailed description and scope of the application may be made by those skilled in the art in light of the teachings of the embodiments of the present invention, which fall within the purview of the appended claims and equivalents thereto.
Claims (9)
1. The synthesis method of the 2-chlorothiophene-5-formic acid is characterized by comprising the following steps:
(1) Under the action of concentrated sulfuric acid, thiophene-2-formic acid and ethanol undergo esterification reaction to generate thiophene-2-ethyl formate;
(2) Chloridizing thiophene-2-ethyl formate with sulfonyl chloride in a methylene dichloride and N, N-dimethylformamide system to generate 2-chlorothiophene-5-ethyl formate;
the operation method of the step (2) comprises the following steps: mixing thiophene-2-ethyl formate, dichloromethane and N, N-dimethylformamide, heating to 35-39 ℃, dropwise adding sulfonyl chloride, carrying out heat preservation reaction for 12-18 h after the dropwise addition, and then evaporating under reduced pressure to obtain 2-chlorothiophene-5-ethyl formate;
(3) Carrying out hydrolysis reaction on the 2-chlorothiophene-5-ethyl formate under the action of alkaline substances to generate 2-chlorothiophene-5-formic acid;
the reaction equation is as follows:
2. the method for synthesizing 2-chlorothiophene-5-carboxylic acid according to claim 1, wherein the operation method of step (1) is as follows:
and mixing thiophene-2-formic acid with ethanol, dropwise adding concentrated sulfuric acid, heating to 75-85 ℃ after the dropwise adding, reacting for 6-10 h, and then performing aftertreatment to obtain the thiophene-2-ethyl formate.
3. The method for synthesizing 2-chlorothiophene-5-carboxylic acid according to claim 2, wherein the mass ratio of thiophene-2-carboxylic acid to ethanol is 1:2-5.
4. The method for synthesizing 2-chlorothiophene-5-carboxylic acid according to claim 2, wherein the mass ratio of thiophene-2-carboxylic acid to concentrated sulfuric acid is 1:0.05-0.15.
5. The method for synthesizing 2-chlorothiophene-5-carboxylic acid according to claim 2, wherein the post-treatment method is as follows: after the reaction is finished, the reaction solution is decompressed and evaporated to dryness, water is added, pH=7-7.5 is adjusted by liquid alkali, methyl tertiary butyl ether is used for extraction, the solvent is evaporated from the extract liquid, and the thiophene-2-ethyl formate is obtained.
6. The method for synthesizing 2-chlorothiophene-5-carboxylic acid according to claim 1, wherein in the step (2), the mass ratio of the thiophene-2-carboxylic acid ethyl ester to the dichloromethane and the N, N-dimethylformamide is 25:100-300:0.15-1.15.
7. The method for synthesizing 2-chlorothiophene-5-carboxylic acid according to claim 1, wherein in the step (2), the molar ratio of thiophene-2-carboxylic acid ethyl ester to sulfonyl chloride is 1:1.21-3.58.
8. The method for synthesizing 2-chlorothiophene-5-carboxylic acid according to claim 1, wherein the operation method of step (3) is as follows:
mixing 2-chlorothiophene-5-ethyl formate with aqueous solution of alkaline substances, reacting for 4-10 h at 30-80 ℃, adding active carbon, stirring for 1-2 h, filtering, cooling filtrate to room temperature, regulating pH=0.5-2.5 with refined hydrochloric acid, cooling to 5-15 ℃, stirring for 2h, filtering, and drying filter cakes to obtain the 2-chlorothiophene-5-formic acid.
9. The method for synthesizing 2-chlorothiophene-5-carboxylic acid according to claim 8, wherein the aqueous solution of the alkaline substance is 15-18 wt% aqueous solution of sodium hydroxide; the mass ratio of the aqueous solution of the alkaline substance to the ethyl 2-chlorothiophene-5-carboxylate is 4-6:1.
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| CN108840854A (en) * | 2018-09-18 | 2018-11-20 | 浙江扬帆新材料股份有限公司 | A kind of method of one pot process 5- chlorothiophene -2- carboxylic acid |
| CN108997305A (en) * | 2018-08-29 | 2018-12-14 | 郑州轻工业学院 | A kind of new compound 3- methyl -4,5- dichloro-thiophene -2- carboxylic acid and preparation method thereof |
| CN110317189A (en) * | 2019-07-19 | 2019-10-11 | 安徽中羰碳一工业技术有限责任公司 | A method of using thiophene -2-carboxylic acid as Material synthesis 5- chlorothiophene -2- formic acid |
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