CN115557928A - Synthetic method of 2-chlorothiophene-5-formic acid - Google Patents
Synthetic method of 2-chlorothiophene-5-formic acid Download PDFInfo
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- CN115557928A CN115557928A CN202211308456.5A CN202211308456A CN115557928A CN 115557928 A CN115557928 A CN 115557928A CN 202211308456 A CN202211308456 A CN 202211308456A CN 115557928 A CN115557928 A CN 115557928A
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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 39
- 238000010189 synthetic method Methods 0.000 title claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 30
- 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 28
- 238000000034 method Methods 0.000 claims abstract description 26
- 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 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 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
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 6
- 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 230000002194 synthesizing effect Effects 0.000 claims description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 6
- 238000001704 evaporation Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 5
- JZGZKRJVTIRPOK-UHFFFAOYSA-N ethyl thiophene-2-carboxylate Chemical compound CCOC(=O)C1=CC=CS1 JZGZKRJVTIRPOK-UHFFFAOYSA-N 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- 230000008020 evaporation Effects 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 9
- 239000002699 waste material Substances 0.000 abstract description 3
- 230000032050 esterification Effects 0.000 abstract description 2
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- GSFNQBFZFXUTBN-UHFFFAOYSA-N 2-chlorothiophene Chemical compound ClC1=CC=CS1 GSFNQBFZFXUTBN-UHFFFAOYSA-N 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
- 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 4
- 229960001148 rivaroxaban Drugs 0.000 description 4
- 239000002351 wastewater Substances 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
- 238000002360 preparation method Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 229950009390 symclosene Drugs 0.000 description 3
- 238000001308 synthesis method Methods 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
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003786 synthesis reaction 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000009286 beneficial effect 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
- 238000011161 development Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- BMOKMXXTOZFEIZ-UHFFFAOYSA-N ethyl 5-chlorothiophene-2-carboxylate Chemical compound CCOC(=O)C1=CC=C(Cl)S1 BMOKMXXTOZFEIZ-UHFFFAOYSA-N 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 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
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
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Classifications
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Abstract
The invention discloses a synthetic method of 2-chlorothiophene-5-formic acid, which comprises the following steps: carrying out esterification reaction on thiophene-2-formic acid and ethanol under the action of concentrated sulfuric acid to generate thiophene-2-ethyl formate; performing chlorination reaction on thiophene-2-ethyl formate and sulfonyl chloride in a dichloromethane and N, N-dimethylformamide system to generate 2-chlorothiophene-5-ethyl formate; 2-chlorothiophene-5-ethyl formate is subjected to hydrolysis reaction under the action of alkaline substances to generate 2-chlorothiophene-5-formic acid; the method takes thiophene-2-formic acid as a raw material, and 2-chlorothiophene-5-formic acid is obtained through esterification, chlorination and hydrolysis, and is novel, simple to operate, cheap and easily available in raw materials and auxiliary materials, mild in reaction, high in selectivity, high in product yield and purity, less in three wastes, more environment-friendly and 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 the anticoagulant rivaroxaban. Rivaroxaban is an oral factor Xa direct inhibitor jointly developed by Bayer and Qiangsheng companies, has highly selective and competitive inhibition effects on free and combined factor Xa, and clinical tests show that rivaroxaban has fewer pharmaceutical parameters and pharmacokinetics and interacts with other drugs, and is rarely influenced by factors such as age, sex and the like of a patient, so that rivaroxaban is an excellent oral anticoagulant.
The 2-chlorothiophene-5-formic acid is synthesized by a method mainly using 2-chlorothiophene or thiophene-2-formic acid as a starting material, wherein the starting material is selected differently.
The synthesis method takes 2-chlorothiophene as a raw material, firstly acidylates and then oxidizes to prepare the 2-chlorothiophene-5-formic acid. Chinese patent CN109422720A uses 2-chlorothiophene as a raw material, formylates to obtain 2-chlorothiophene-5-formaldehyde, and oxidizes to obtain 2-chlorothiophene-5-formic acid, and mainly aims to generate large treatment capacity of phosphorus wastewater, and a synthesis route is as follows:
chinese patent CN 102993164A uses 2-chlorothiophene as a raw material, acetylates the raw material to obtain 2-chlorothiophene-5-acetyl, and oxidizes the acetyl to obtain 2-chlorothiophene-5-formic acid, and mainly aims to obtain the following synthetic route:
patent documents RSC Advances 2014,4 (26), 13430-13433 take 2-chlorothiophene as a raw material, react with carbon dioxide, LDA is used as a catalyst, and then acidification is carried out to obtain 2-chlorothiophene-5-formic acid, wherein the reaction conditions are harsh, the LDA is high in price and large in danger, and is not suitable for scale-up production, and the synthetic route is as follows:
chinese patent CN 110317189B uses thiophene-2-formic acid as a raw material and trichloroisocyanuric acid as a chlorinating agent to obtain 2-chlorothiophene-5-formic acid. The method is simple to operate, violent in reaction, and easy to generate byproducts such as 3-chlorothiophene-5-formic acid by strictly controlling the feeding speed and the reaction temperature of the trichloroisocyanuric acid, the amount of generated acid wastewater is large, and the residual trichloroisocyanuric acid in the wastewater needs to be paid attention before being discharged into a wastewater pool, so that the generation of nitrogen trichloride is avoided, combustion and explosion occur, and the synthetic route is as follows:
in conclusion, the development of the method which is beneficial to environmental protection, low in cost, good in quality, simple in operation and high in safety and can be applied to production amplification is a method for synthesizing and preparing 2-chlorothiophene-5-formic acid and needs intensive research.
Disclosure of Invention
The invention provides a novel synthesis method of 2-chlorothiophene-5-formic acid, which comprises the steps of esterifying thiophene-2-formic acid, reacting with a chlorination reagent sulfonyl chloride which is cheap and easy to obtain and mild in reaction conditions, and hydrolyzing with alkali to obtain a product.
The technical scheme of the invention is as follows:
a method for synthesizing 2-chlorothiophene-5-formic acid comprises the following steps:
(1) Thiophene-2-formic acid and ethanol are subjected to esterification reaction under the action of concentrated sulfuric acid (98 wt%) to generate thiophene-2-ethyl formate;
(2) Performing chlorination reaction on thiophene-2-ethyl formate and sulfonyl chloride in a dichloromethane and N, N-dimethylformamide system to generate 2-chlorothiophene-5-ethyl formate;
(3) 2-chlorothiophene-5-ethyl formate is subjected to hydrolysis reaction under the action of alkaline substances to generate 2-chlorothiophene-5-formic acid.
Specifically, the operation method of the step (1) comprises the following steps:
mixing thiophene-2-formic acid with ethanol, dropwise adding concentrated sulfuric acid, heating to 75-85 ℃ after dropwise adding, reacting for 6-10 h, and then carrying out 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;
the post-treatment method comprises the following steps: and after the reaction is finished, evaporating the reaction solution under reduced pressure, adding water, adjusting the pH to be 7-7.5 by using liquid alkali, extracting by using methyl tert-butyl ether, evaporating the extraction solution to remove the solvent, and drying to obtain the thiophene-2-ethyl formate.
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, reacting for 12-18 h while keeping the temperature, and then evaporating to dryness under reduced pressure to obtain 2-chlorothiophene-5-ethyl formate;
the mass ratio of the thiophene-2-ethyl formate to the dichloromethane and the N, N-dimethylformamide is 25;
the molar ratio of the thiophene-2-carboxylic acid ethyl ester to the sulfonyl chloride is 1.21-3.58, preferably 1.
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 h (preferably 4-6 h) at 30-80 ℃ (preferably 50-80 ℃), adding activated carbon, stirring for 1-2 h, filtering, cooling the filtrate to room temperature, adjusting the pH = 0.5-2.5 with refined hydrochloric acid, cooling to 5-15 ℃, stirring for 2h, filtering, and drying a filter cake to obtain 2-chlorothiophene-5-formic acid;
the aqueous solution of the alkaline substance is preferably an aqueous solution of 15 to 18wt% of sodium hydroxide; the mass ratio of the aqueous solution of the alkaline substance to the 2-chlorothiophene-5-ethyl formate is 4-6:1, preferably 5-6:1;
preferably, the mass ratio of the activated carbon to the 2-chlorothiophene-5-ethyl formate is 0.03-0.08;
the mass ratio of the purified hydrochloric acid to the 2-chlorothiophene-5-carboxylic acid ethyl ester is 1.4 to 2.5, preferably 1.6 to 1.8.
The reaction equation of the present invention is as follows:
the innovation of the invention is that: esterification using thiophene-2-formic acid as raw material can improve the chlorination activity of sulfonyl chloride as a chlorinating agent, and 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 obtained raw and auxiliary materials, high reaction selectivity, high yield, less three wastes, and environmental protection, and is suitable for large-scale production, and the generated waste gas mainly comprising the three wastes can be absorbed by alkaline water.
Drawings
FIG. 1 shows the NMR spectrum of 2-chlorothiophene-5-carboxylic acid prepared according to the invention.
FIG. 2 is the NMR carbon spectrum of 2-chlorothiophene-5-carboxylic acid prepared according to the invention.
Detailed Description
The invention is further described below by means of specific examples, without the scope of protection of the invention being limited thereto.
Example 1:
preparation of thiophene-2-ethyl formate: 30g of thiophene-2-formic acid and 120g of ethanol are added into a 250ml reaction bottle, stirred and dissolved, 2.55g of concentrated sulfuric acid is dripped in, the temperature is raised to 80 ℃ after the dripping is finished, the reaction is kept for 6 hours, the solvent is concentrated until no flow exists, the temperature is reduced to room temperature, water is added, 24.2g of liquid alkali is used for adjusting the pH value to 7.5, 3 times 30ml of methyl tert-butyl ether is used for extraction, and the distillation is carried out, so that 34.13g of thiophene-2-ethyl formate is obtained, the yield is 89.79 percent, and the purity is 99.46 percent. 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)。
Preparing 2-chlorothiophene-5-ethyl formate: adding 25g (0.16 mol) of thiophene-2-ethyl formate, 300ml of dichloromethane and 0.6g of N, N-dimethylformamide into a reaction vessel, heating to 35 ℃, dropwise adding 54g (0.4 mol) of sulfonyl chloride, keeping the temperature at 35-39 ℃ for reaction for 15 hours after dropwise adding, and distilling the solvent until no flow exists to obtain 30.41g of 2-chlorothiophene-5-ethyl formate, wherein 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)。
Preparing 2-chlorothiophene-5-formic acid: adding 135g of 16.7 percent sodium hydroxide aqueous solution into a reaction vessel of 30g of 2-chlorothiophene-5-ethyl formate, heating to 65-75 ℃, keeping the temperature for reaction for 4 hours, adding 1g of activated carbon, stirring for 1 hour, filtering, cooling the filtrate to room temperature, dropwise adding 42.5g of refined hydrochloric acid to adjust the pH value 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 percent and the yield of 82.47. [ M-H ]] - ＝160.7， 1 H NMR(DMSO-d6；δ H =2.489 ppm), nuclear magnetic resonance hydrogen spectrum (fig. 1):
s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet, dt = 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 for dissolving, dripping 2.55g of concentrated sulfuric acid, heating to 80 ℃ after dripping, keeping the temperature for reaction for 6 hours, concentrating the solvent until no flow exists, cooling to room temperature, adding water, adjusting the pH value to 7.5 by using 24.2g of liquid alkali, extracting for 3 times by using 3 x 30ml of methyl tert-butyl ether, and distilling to obtain 33.95g of thiophene-2-ethyl formate, wherein the yield is 89.32 percent and the purity is 99.52 percent;
preparing 2-chlorothiophene-5-ethyl formate: adding 25g (0.16 mol) of thiophene-2-ethyl formate, 300ml of dichloromethane, 0.6g of N, N-dimethylformamide into a reaction vessel, heating to 35 ℃, dropwise adding 52g (0.39 mol) of sulfonyl chloride, keeping the temperature at 35-39 ℃ for reaction for 15 hours after dropwise adding, and distilling the solvent until no flow exists to obtain 30.36g of 2-chlorothiophene-5-ethyl formate, wherein the yield is 99.5%, and the purity is 99.62%.
Preparing 2-chlorothiophene-5-formic acid: adding 135g of 16.7 percent sodium hydroxide aqueous solution into a reaction vessel of 30g of 2-chlorothiophene-5-ethyl formate, heating to 65-75 ℃, keeping the temperature and reacting for 4 hours, adding 1g of activated carbon, stirring for 1 hour, filtering, cooling the filtrate to room temperature, dropwise adding 42.5g of refined hydrochloric acid to adjust the pH value 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 percent and the yield of 80.51 percent.
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 for dissolving, dripping 2.55g of concentrated sulfuric acid, heating to 80 ℃ after dripping is finished, carrying out heat preservation reaction for 6 hours, concentrating a solvent until no flow exists, cooling to room temperature, adding water, adjusting the pH value to 7.5 by using 24.2g of liquid alkali, extracting for 3 times by using 3 x 30ml of methyl tert-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%;
preparing 2-chlorothiophene-5-ethyl formate: adding 25g (0.16 mol) of thiophene-2-ethyl formate, 300ml of dichloromethane and 0.6g of N, N-dimethylformamide into a reaction vessel, heating to 35 ℃, dropwise adding 56g (0.41 mol) of sulfonyl chloride, keeping the temperature at 35-39 ℃ for reaction for 15 hours after completing dropwise addition, and distilling the solvent until no flow exists to obtain 30.4g of 2-chlorothiophene-5-ethyl formate, wherein the yield is 99.63% and the purity is 99.6%.
Preparing 2-chlorothiophene-5-formic acid: adding 135g of 16.7 percent sodium hydroxide aqueous solution into a reaction vessel of 30g of 2-chlorothiophene-5-ethyl formate, heating to 65-75 ℃, preserving heat for reaction for 4 hours, adding 1g of activated carbon, stirring for 1 hour, filtering, cooling the filtrate to room temperature, dropwise adding 42.5g of refined hydrochloric acid to adjust the pH value to 0.5, cooling to 5-15 ℃, stirring for 2 hours, filtering and drying to obtain 20.9g of 2-chlorothiophene-5-formic acid with the purity of 99.84 percent and the yield of 81.69.
The present invention has been described in detail with reference to the specific embodiments thereof, but the description should not be construed as limiting the invention. Modifications and variations in the particular embodiments and applications of the method according to the embodiments of the invention will occur to those skilled in the art, provided they come within the scope of the appended claims and their equivalents.
Claims (10)
1. A synthetic method of 2-chlorothiophene-5-formic acid is characterized by comprising the following steps:
(1) Carrying out esterification reaction on thiophene-2-formic acid and ethanol under the action of concentrated sulfuric acid to generate thiophene-2-ethyl formate;
(2) Performing chlorination reaction on thiophene-2-ethyl formate and sulfonyl chloride in a dichloromethane and N, N-dimethylformamide system to generate 2-chlorothiophene-5-ethyl formate;
(3) 2-chlorothiophene-5-ethyl formate is subjected to hydrolysis reaction 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:
mixing thiophene-2-formic acid with ethanol, dropwise adding concentrated sulfuric acid, heating to 75-85 ℃ after dropwise adding, reacting for 6-10 h, and then carrying out aftertreatment to obtain 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 to 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.
5. The method for synthesizing 2-chlorothiophene-5-carboxylic acid according to claim 2, wherein the post-treatment method comprises the following steps: and after the reaction is finished, decompressing and evaporating the reaction liquid, adding water, adjusting the pH = 7-7.5 by using liquid alkali, extracting by using methyl tert-butyl ether, evaporating the extraction liquid to remove the solvent, and drying to obtain the thiophene-2-ethyl formate.
6. The method for synthesizing 2-chlorothiophene-5-carboxylic acid according to claim 1, wherein the operation method of step (2) is:
mixing thiophene-2-ethyl formate, dichloromethane and N, N-dimethylformamide, heating to 35-39 ℃, dropwise adding sulfonyl chloride, reacting for 12-18 hours in a heat preservation manner after dropwise adding, and then performing reduced pressure evaporation to obtain the 2-chlorothiophene-5-ethyl formate.
7. The method for synthesizing 2-chlorothiophene-5-carboxylic acid according to claim 6, wherein the mass ratio of thiophene-2-carboxylic acid ethyl ester to dichloromethane and N, N-dimethylformamide is 25-300.
8. The method for synthesizing 2-chlorothiophene-5-carboxylic acid according to claim 6, wherein the molar ratio of thiophene-2-carboxylic acid ethyl ester to sulfonyl chloride is 1.21-3.58.
9. The method for synthesizing 2-chlorothiophene-5-carboxylic acid according to claim 2, wherein the operation method of step (3) is:
mixing 2-chlorothiophene-5-ethyl formate with an aqueous solution of an alkaline substance, reacting for 4-10 h at 30-80 ℃, adding activated carbon, stirring for 1-2 h, filtering, cooling the filtrate to room temperature, adjusting the pH = 0.5-2.5 with refined hydrochloric acid, cooling to 5-15 ℃, stirring for 2h, filtering, and drying a filter cake to obtain 2-chlorothiophene-5-formic acid.
10. The method for synthesizing 2-chlorothiophene-5-carboxylic acid as claimed in claim 9, wherein the aqueous solution of the basic substance is an aqueous solution of 15 to 18% by weight of sodium hydroxide; the mass ratio of the aqueous solution of the alkaline substance to the 2-chlorothiophene-5-ethyl formate is 4-6:1.
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| 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 |
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