CN109053677B - Preparation method of aromatic benzothiophene-1, 1-dioxide - Google Patents
Preparation method of aromatic benzothiophene-1, 1-dioxide Download PDFInfo
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- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
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Abstract
The invention provides a preparation method of aromatic benzothiophene-1, 1-dioxide, which comprises the following steps: cyclizing an ortho-substituted aromatic ring and sodium alkyl sulfinate in one step, and performing dehydration reaction to obtain aromatic ring bithiophene-1, 1-dioxide; the ortho-substituted aromatic ring has the structure of the compound shown in the formula (I); compared with the synthetic route of the existing method, the preparation method of the aromatic benzothiophene-1, 1-dioxide provided by the invention has the advantages of easily available raw materials, low cost, mild reaction, easy control, less three wastes, less pollution and simple post-treatment, is suitable for preparing almost all types of aromatic benzothiophene-1, 1-dioxide, provides a new strategy for the aromatic benzothiophene-1, 1-dioxide, and has higher production and application values.
Description
Technical Field
The invention belongs to the field of synthesis of medical intermediates, and relates to a preparation method of aromatic benzothiophene-1, 1-dioxide.
Background
The compound has high reaction activity and wide application in medicine synthesis.
Currently, the main synthesis methods of the aromatic benzothiophene-1, 1-dioxide include the following methods: (1) the final product is obtained by multiple reactions of lithiation nucleophilic substitution, oxidation, intramolecular cyclization, elimination and the like of o-bromomethyl sulfide, but the method has long route, and the raw materials and the intermediates are very smelly thioether, so that the method has large environmental pollution and is not beneficial to production and environmental protection; (2) aromatic benzothiophene or aromatic benzothiophene-1-oxide is oxidized by oxidants such as hydrogen peroxide, tert-butyl hydroperoxide, m-chloroperoxybenzoic acid or potassium peroxymonosulfate to obtain a final product, but the raw materials of the method are not easy to obtain, the preparation of the raw materials needs to be subjected to multi-step reaction, and the process is complex; (3) o-diazophenylacetylene reacts with sulfur dioxide, and a final product is obtained through cyclization, but the o-diazophenylacetylene serving as a raw material of the reaction is expensive and is not easy to obtain; (4) the styrene sulfonyl chloride is obtained by intramolecular cyclization similar to Friedel-crafts reaction, and the styrene sulfonyl chloride used as the raw material of the method is difficult to prepare and can be obtained only by multi-step reaction.
Therefore, the existing synthesis method of the aromatic ring bithiophene-1, 1-dioxide has the problems of complex preparation process, great environmental pollution of preparation raw materials and intermediates and difficult obtainment of the preparation raw materials. How to develop a method with easily obtained raw materials, few reaction steps and environment-friendly synthesis process has important significance and value.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a preparation method of aromatic benzothiophene-1, 1-dioxide.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a preparation method of aromatic benzothiophene-1, 1-dioxide, which comprises the following steps: cyclizing an ortho-substituted aromatic ring and sodium alkyl sulfinate in one step, and performing dehydration reaction to obtain aromatic ring bithiophene-1, 1-dioxide;
the ortho-substituted aromatic ring has the structure of a compound shown as a formula I:
wherein n ring is a substituted or unsubstituted aromatic ring, X is a halogen atom, R1Is hydrogen, C1-C20Linear alkyl (which may be methyl, ethyl, propyl, butyl, dodecyl, hexadecyl or eicosyl, for example) or C3-C20The branched alkyl group (which may be, for example, an isopropyl group, a cyclopropyl group, a sec-butyl group, a tert-butyl group or an isoeicosyl group).
Compared with the synthetic route of the existing method, the preparation method of the aromatic ring bithiophene-1, 1-dioxide provided by the invention has the advantages of easily available raw materials, low cost, mild reaction, easy control, less three wastes, less pollution and simple post-treatment, and is suitable for preparing almost all kinds of aromatic ring bithiophene-1, 1-dioxide.
In the cyclization reaction of the compound shown in the formula (I) and sodium alkylsulfinate, the reaction of removing hydrogen halide of halogen atoms and sodium sulfinate and the dehydration reaction of alkyl and carbonyl are carried out simultaneously, the reaction is completed in one step, the manpower and material resources are saved, the reaction efficiency is high, the product yield can reach more than 50%, wherein the highest yield reaches 94.5%.
In the invention, the sodium alkylsulfinate has the structure R2CH2SO2Na wherein R2Is hydrogen, C1-C20Linear alkyl (which may be methyl, ethyl, propyl, butyl, dodecyl, hexadecyl or eicosyl, for example) or C3-C20The branched alkyl group (which may be, for example, an isopropyl group, a cyclopropyl group, a sec-butyl group, a tert-butyl group or an isoeicosyl group).
Preferably, in the ortho-substituted aromatic ring, the n ring is any one of an unsubstituted or substituted benzene ring, an unsubstituted or substituted pyridine ring, an unsubstituted or substituted pyrimidine ring, an unsubstituted or substituted pyrazine ring, an unsubstituted or substituted pyridazine ring, an unsubstituted or substituted thiophene, an unsubstituted or substituted furan, an unsubstituted or substituted thiazole, an unsubstituted or substituted imidazole, or an unsubstituted or substituted pyrazole.
Preferably, when the n-ring is a substituted n-ring, the substituents in the n-ring include any one or a combination of at least two of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, trifluoromethyl, nitro, amino, dimethylamino, diethylamino, acetyl, acetylamino, acetoxy, methylsulfonylamino, ethylsulfonamido, methylsulfonyloxy, ethylsulfonyloxy, carboxyl, methoxycarbonyl, formyl, ethoxycarbonyl, isopropoxycarbonyl, cyano, methylsulfonyl, hydroxyl, trifluoromethoxy, ethoxy, isopropoxy, or n-butoxy, with typical but not limiting combinations being: fluorine and chlorine; n-butyl, trifluoromethyl and nitro; hydroxyl, bromo and acetyl.
Preferably, X is any one of fluorine, chlorine, bromine or iodine.
Preferably, the one-step cyclization process is as follows: under the protection of protective atmosphere, sodium alkylsulfinate and a compound shown as a formula (I) are dispersed in a first reaction solvent to carry out one-step cyclization reaction.
In the invention, one-step cyclization reaction of the sodium alkylsulfinate and the compound shown in the formula (I), reaction of halogen atoms and sodium sulfinate and reaction of alkyl and carbonyl are carried out simultaneously, and the reaction is completed in one step.
Preferably, the gas of the protective atmosphere comprises nitrogen and/or argon.
Preferably, the molar ratio of the sodium alkylsulfinate to the compound of formula (I) in the one-step cyclization reaction is (0.5-10: 1), and may be, for example, 0.5:1, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 or 10:1, preferably (1-2: 1).
In the present invention, the molar ratio of the sodium alkylsulfinate to the compound represented by the formula (I) is specified, and when the reaction molar ratio is not within a limited range, the yield of the reaction may be decreased.
Preferably, the temperature of the one-step cyclization reaction is 50-250 ℃, for example, 50 ℃, 80 ℃, 100 ℃, 120 ℃, 150 ℃, 180 ℃, 220 ℃, 240 ℃ or 250 ℃, preferably 100-.
In the present invention, the temperature of the one-step cyclization reaction is specified, and when the reaction temperature is not within a limited range, the yield of the reaction is lowered.
Preferably, the first reaction solvent comprises any one of or a combination of at least two of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoramide, methanol, ethanol, isopropanol, acetonitrile and 1, 4-dioxane, wherein a typical but non-limiting combination is: dimethyl sulfoxide and N, N-dimethylformamide; methanol and acetonitrile; dimethyl sulfoxide, methanol and 1, 4-dioxane; dimethyl sulfoxide or N, N-dimethylformamide is preferred.
In the present invention, the first reaction solvent is not limited to the above-exemplified solvents.
In the present invention, dimethyl sulfoxide or N, N-dimethylformamide is preferably used as a solvent to increase the reaction yield, but the reaction yield is decreased by using other solvents.
Preferably, in the one-step cyclization process, 2 to 50mL of the reaction solvent, for example, 2mL, 5mL, 10mL, 20mL, 30mL, 40mL or 50mL, is added to 1g of the compound represented by formula (I), and preferably 5 to 10mL of the reaction solvent is added to 1g of the compound represented by formula (I).
Preferably, the dehydration reaction is carried out by: and mixing the product obtained after the one-step cyclization reaction, methanesulfonyl chloride and alkali in a second reaction solvent, and performing dehydration reaction to obtain the aromatic benzothiophene-1, 1-dioxide.
Preferably, the molar ratio of the product after the one-step cyclization reaction, the methanesulfonyl chloride and the base is 1 (1-5): (1-5), and may be, for example, 1:1:1, 1:2:3, 1:3:2, 1:3:3, 1:3:4, 1:4:4 or 1:5:5, preferably 1:2: 3.
In the present invention, by using the above-mentioned reaction molar ratio, the product yield can be maximized, and particularly, when the molar ratio of the product after the one-step cyclization reaction, methanesulfonyl chloride and base is 1:2:3, the reaction effect is optimized.
Preferably, the base comprises any one of sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, sodium methoxide, sodium ethoxide, or potassium tert-butoxide, or a combination of at least two of them, with a typical but non-limiting combination being: sodium and potassium carbonate; triethylamine and diisopropylethylamine; potassium carbonate, cesium carbonate and triethylamine; triethylamine is preferred.
Preferably, the second reaction solvent comprises any one of or a combination of at least two of dichloromethane, chloroform, ethyl acetate, isopropyl acetate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1, 4-dioxane, toluene, acetonitrile, acetone, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, N-dimethylformamide, or hexamethylphosphoramide, wherein a typical but non-limiting combination is: dichloromethane and chloroform; dimethyl sulfoxide and N, N-dimethylformamide; 1, 4-dioxane, toluene and acetonitrile; preferably dichloromethane.
In the present invention, the second reaction solvent is not limited to the above-exemplified solvents.
Preferably, 5 to 50mL of the second reaction solvent, for example, 5mL, 10mL, 20mL, 25mL, 30mL, 35mL, 40mL, 45mL, or 50mL, is added to 1g of the product after the one-step cyclization reaction in the course of the dehydration reaction.
Preferably, the dehydration reaction temperature is-20 to 50 ℃, for example-20 ℃, -15 ℃, -10 ℃, -5 ℃, 0 ℃,10 ℃, 20 ℃, 30 ℃, 40 ℃ or 50 ℃, preferably 0 to 25 ℃.
The preparation method of the aromatic ring bithiophene-1, 1-dioxide provided by the invention specifically comprises the following steps:
(1) dissolving sodium alkylsulfinate and a compound shown as a formula (I) in a molar ratio of (0.5-10):1 in a reaction solvent under a protective atmosphere, and performing one-step cyclization reaction at 50-250 ℃ to obtain a one-step cyclization reaction solution;
(2) carrying out post-treatment on the one-step cyclization reaction liquid to obtain a product after one-step cyclization reaction;
(3) carrying out dehydration reaction on a product obtained after the one-step cyclization reaction with the molar ratio of 1 (1-5) to (1-5), methanesulfonyl chloride and alkali in a reaction solvent at the temperature of-20-50 ℃ to obtain a dehydration reaction solution;
(4) and carrying out post-treatment on the dehydrated reaction solution to obtain the aromatic benzothiophene-1, 1-dioxide.
Preferably, the post-treatment of step (2) and step (4) comprises any one or a combination of at least two of extraction, washing, purification, filtration and drying.
Preferably, the post-treatment in step (2) comprises sequentially extracting, washing, drying, concentrating and purifying to obtain a product after one-step cyclization reaction.
Preferably, the post-treatment in the step (4) comprises the steps of sequentially extracting, washing, drying and purifying to obtain the aromatic ring bithiophene-1, 1-dioxide.
Preferably, the purification method includes any one or a combination of at least two of column chromatography, distillation under reduced pressure, and recrystallization.
The preparation method provided by the invention has the following specific reaction formula:
compared with the prior art, the invention has the following beneficial effects:
(1) compared with the synthetic route of the existing method, the preparation method of the aromatic ring bithiophene-1, 1-dioxide provided by the invention has the advantages of easily available raw materials, low cost, mild reaction, easy control, less three wastes, less pollution and simple post-treatment, and is suitable for preparing almost all kinds of aromatic ring bithiophene-1, 1-dioxide.
(2) In the preparation method of the aromatic ring bithiophene-1, 1-dioxide, the compound shown in the formula (I) and the sodium alkylsulfinate can form rings in one step, so that manpower and material resources are saved, the reaction efficiency is high, the product yield can reach more than 50%, wherein the highest yield reaches 94.5%.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
In the following examples, the reagents used are commercially available, where EA is ethyl acetate, PE is petroleum ether, DCM is dichloromethane, TEA is triethylamine, and DMSO is dimethyl sulfoxide.
Example 1
This example prepares an arylthienothiophene-1, 1-dioxide by the following reaction, where the n-ring in formula (I) is benzeneRing, X is F, R1、R2Hydrogen, the reaction formula is as follows:
(1)20.0g of 2-fluorobenzaldehyde (0.161mol, 1.0eq) and 33g of sodium methylsulfinate (0.323mol, 2.0eq) were charged in a 250mL round-bottomed flask containing 130mL of dimethyl sulfoxide, and the mixture was replaced with nitrogen three times and stirred overnight at 100 ℃ under a nitrogen atmosphere. And (4) detecting the reaction by TLC, stopping heating, cooling to room temperature, pouring into about 800mL of ice water, and detecting no byproduct point by a point plate. The ethyl acetate was extracted three times at 200mL, the organic phases were combined and washed three times with 50mL of saturated sodium chloride. Drying the organic phase with anhydrous sodium sulfate, passing through a silica gel pad, spin-drying, mixing with silica gel, and performing silica gel column chromatography to obtain yellow oily matter 1 about 28g with yield of about 94.5%;
mass spectrum of compound 1: 184.0 for [ M ];
nuclear magnetic resonance hydrogen spectrum of compound 1:1H NMR(400MHz,CDCl3)δ7.74–7.46(m,4H),5.45(dd,J＝6.8,4.6Hz,1H),3.74(dd,J＝13.6,6.8Hz,1H),3.71(br s,1H),3.38(dd,J＝13.6,4.6Hz,1H)。
(2) 30.0g of compound 1(0.163mol, 1.0eq) and 82.5g of triethylamine (0.815mol, 5.0eq) are added into a 500mL three-necked round-bottomed flask containing 300mL of DCM, 37.3g of methanesulfonyl chloride (0.326mol, 2.0e q) is slowly added dropwise, the temperature is controlled to be not higher than 10 ℃, after the dropwise addition is finished, the system is heated to room temperature and stirred for 5 hours, and the plate is dropped until the raw materials disappear. Stirring is stopped, about 200mL of water is poured, stirring and layering are carried out, extraction is carried out, 200mL of DCM is used for extraction for three times, organic phases are combined, 100mL of saturated sodium bicarbonate is washed once, and 50mL of saturated sodium chloride is washed twice. The organic phase was dried, filtered through a pad of silica gel, spin dried, and the crude product was slurried with 100mL of methanol in an ice water bath and filtered to give 2 about 23g of a yellow solid with a yield of about 85.0%.
Mass spectrum of compound 2: [ M ] ═ 166.0;
nuclear magnetic resonance hydrogen spectrum of compound 2:1H NMR(400MHz,CDCl3)δ7.77–7.72(m,1H),7.62-7.52(m,2H),7.42-7.36(m,1H),7.25(dd,J＝6.9,0.8Hz,1H),6.75(d,J＝6.9Hz,1H)。
example 2
This example prepares an arylthienothiophene-1, 1-dioxide by the reaction where in formula (I) the n ring is a benzene ring, X is F, R is1Is methyl, R2Hydrogen, the reaction formula is as follows:
(1) 3g of o-fluoro acetophenone (0.021mol, 1eq) and 4.5g of sodium methyl sulfinate (0.04mol, 2eq) are added into a 50mL single-mouth bottle, then 21mL of DMSO is added, then the mixture is stirred for 10min, heated, reacted at the external temperature of 150 ℃ and the internal temperature of 130 ℃ for 16h, the TLC detection reaction is completed, cooled, poured into 80mL of ice water and extracted with 100mL of ethyl acetate for 2 times, organic phases are combined, 50mL of saturated saline is washed for 3 times, dried and subjected to sample mixing and column chromatography (PE: EA is 3:1) to obtain about 3.1g of light yellow solid, and the yield is 74.5%.
Nuclear magnetic resonance hydrogen spectrum of compound 3:1H NMR(400MHz,CDCl3)δ7.76–7.66(m,3H),7.63–7.57(m,1H),3.69–3.54(m,2H),2.67(br s,1H),1.82(s,3H)。
(2) adding 0.5g of product 3(0.003mol, 1eq) and 1.6g of TEA (0.015mol, 5eq) into a 25mL single-neck bottle containing 5mL of DCM, cooling to below 10 ℃, slowly adding 0.7g of methylsulfonyl chloride (0.006mol, 2eq), after dropping, stirring for 30min, TLC (PE: EA is equal to 3:1, Rf is equal to 0.2, and Rf is equal to 0.5), stopping stirring completely, adding 4mL of water, performing layer extraction, performing 4mL extraction of DCM for 2 times, combining organic phases, washing with saturated sodium bicarbonate (10mL), washing with saturated salt water (10mL), drying, and performing column chromatography (PE: EA is equal to 3:1) to obtain 0.3g of product, wherein the yield is about 66.0%.
Mass spectrum of compound 4: [ M ] ═ 180.0;
nuclear magnetic resonance hydrogen spectrum of compound 4:1H NMR(400MHz,CDCl3)δ7.74(d,J＝7.5,1H),7.63(td,J＝7.5,1.2Hz,1H),7.57(td,J＝7.5,1.2Hz,1H),7.44(d,J＝7.5Hz,1H),6.50(q,J＝1.6Hz,1H),2.30(d,J＝1.6Hz,3H)。
example 3
This example prepares the aromatic ring by the following reactionAnd thiophene-1, 1-dioxide, wherein in formula (I), n ring is bromobenzene, X is F, R1、R2Hydrogen, the reaction formula is as follows:
(1) adding 2.03g (0.01mol, 1eq) of 5-bromo-2-fluorobenzaldehyde and 2.04g (0.02mol, 2eq) of sodium methylsulfinate into a 50mL single-neck flask, then adding 14mL of DMSO, stirring for 10min, heating, reacting at an external temperature of 115 ℃ and an internal temperature of 100 ℃ for 16h, detecting by TLC that the reaction is complete, cooling, pouring 80mL of ice water, extracting by EA 100mL for 2 times, combining organic phases, washing by 50mL of saturated saline solution for 3 times, drying, and carrying out column chromatography (PE: EA is 3:1) to obtain 5 about 2.0g of a product, wherein the yield is 76.4%.
Mass spectrum of compound 5: [ M-1 ]]-＝260.6；
Nuclear magnetic resonance hydrogen spectrum of compound 5:1H NMR(400MHz,DMSO)δ7.88(d,J＝1.6Hz,1H),7.83(dd,J＝8.2,1.6Hz,1H),7.75(d,J＝8.2Hz,1H),6.41(d,J＝6.0Hz,1H),5.42(dd,J＝12.0,6.0Hz,1H),4.03(dd,J＝13.6,7.0Hz,1H),3.37(dd,J＝13.6,5.0Hz,1H)。
(2) a 25mL single-neck bottle is filled with 0.5g of compound 5(0.003mol, 1eq), 1.6g of TEA (0.015mol, 5eq) and 5mL of DCM, the temperature is controlled to be lower than 10 ℃, 1.75g of methylsulfonyl chloride (0.015mol, 5eq) is slowly added dropwise, stirring is carried out for 0.5h after dropwise addition is finished, TLC (PE: EA is 3:1 and Rf is 0.5) is completely reacted, stirring is stopped, 4mL of water is added, liquid separation is carried out by stirring, 4mL of DCM is extracted for 2 times, organic phases are combined, saturated sodium bicarbonate (10mL) is washed, saturated salt water is washed (10mL), drying and spin-drying are carried out, column chromatography (PE: EA is 3:1) is carried out, 0.36mg of a product is obtained, and the yield is 76.7%.
Mass spectrum of compound 6: [ M +1 ]]+＝245.7；
Nuclear magnetic resonance hydrogen spectrum of compound 6:1H NMR(400MHz,CDCl3)δ7.70(dd,J＝8.0,1.5Hz,1H),7.61(d,J＝8.0Hz,1H),7.55(d,J＝1.5Hz,1H),7.20(d,J＝6.9Hz,1H),6.79(d,J＝6.9Hz,1H)。
example 4
This example prepares the arylthienothiophene-1, 1-dioxide by the following reaction,wherein n ring in formula (I) is trifluoromethyl benzene, X is F, R1、R2Hydrogen, the reaction formula is as follows:
(1) adding 1.92g (0.01mol, 1eq) of 5-trifluoromethyl-2-fluorobenzaldehyde and 2.04g (0.02mol, 2eq) of sodium methanesulfinate into a 50mL single-neck bottle, then adding 14mL of DMSO, stirring for 10min, heating, reacting at the internal temperature of 115 ℃ for 16h, reacting at the internal temperature of 100 ℃, cooling, pouring 80mL of ice water, extracting for 2 times by 100mL of EA, combining organic phases, washing for 3 times by 50mL of saturated saline water, drying, and carrying out silica gel column chromatography (PE: EA 3:1) to obtain a light yellow solid 7 of about 1.7g with the yield of 67.5%.
Mass spectrum of compound 7: [ M-1 ]]-＝250.9；
Nuclear magnetic resonance hydrogen spectrum of compound 7:1H NMR(400MHz,DMSO)δ8.08–7.98(m,3H),6.50(d,J＝5.8Hz,1H),5.51(dd,J＝11.8,5.8Hz,1H),4.11(dd,J＝13.7,7.0Hz,1H),3.45(dd,J＝13.7,4.9Hz,1H)。
(2) adding 20mL of DCM, 2g of compound 7(7.9mmol,1.0eq) and 4.01g of triethylamine (39.6mmol,5.0eq) into a 100mL three-necked bottle, cooling to 10 ℃, slowly adding 1.82g of methanesulfonyl chloride (15.9mmol, 2.0eq, controlling the temperature to be not higher than 10 ℃), reacting for 30min at 0-10 ℃ after finishing dropping, naturally returning to room temperature, reacting for 4h, completing TLC reaction, adding 20mL of water, separating liquid, extracting for 2 times with 20mL of DCM in water phase, combining organic phases, washing for 1 time with 20mL of saturated sodium bicarbonate, drying, and pulping at low temperature with methanol to obtain 1.3g of yellow solid 8, wherein the yield is 70%.
Mass spectrum of compound 8: [ M +1 ]]+＝235.0；
Nuclear magnetic resonance hydrogen spectrum of compound 8:1H NMR(400MHz,CDCl3)δ7.86(q,J＝8.0Hz,2H),7.66(s,1H),7.31(d,J＝7.0Hz,1H),6.88(d,J＝7.0Hz,1H)。
example 5
This example prepares an arylthienothiophene-1, 1-dioxide by the reaction where in formula (I) the n ring is nitrobenzene and X isF，R1、R2Hydrogen, the reaction formula is as follows:
(1) adding 5g (0.03mol, 1eq) of 2-fluoro-5-nitrobenzaldehyde and 6g (0.059mol, 2eq) of sodium methanesulfinate into a 50mL single-mouth bottle, then adding 30mL of DMSO, stirring for 10min, heating, reacting for 16h at 100 ℃, completing TLC reaction, cooling, pouring 80mL of ice water, extracting twice with 100mL of EA, combining organic phases, washing for three times with 100mL of saturated saline solution, drying, mixing with a sample, and performing silica gel column chromatography (PE: EA is 3:1) to obtain a light yellow solid 9 with the mass of 4.8g and the yield of 71.0%.
Mass spectrum of compound 9: (ii) [ M ] ═ 229.0;
nuclear magnetic resonance hydrogen spectrum of compound 9:1H NMR(400MHz,DMSO)δ8.45(d,J＝2.0Hz,1H),8.42(dd,J＝8.5,2.0Hz,1H),8.09(d,J＝8.4Hz,1H),6.60(d,J＝5.8Hz,1H),5.57-5.49(m,1H),4.16(dd,J＝13.7,7.0Hz,1H),3.50(dd,J＝13.7,5.0Hz,1H)。
(2) in a 50mL single vial, compound 9(0.48g,2.1mmol,1.0eq), TEA (1.06g,10.5mmol,5.0eq) and DCM 15mL were added, the temperature was reduced to 10 ℃ or below, methanesulfonyl chloride (0.48g,4.2mmol,2.0eq) was slowly added, after completion of the addition, the mixture was stirred at room temperature for 30min, TLC (PE: EA ═ 3:1, Rf 0.1, ═ 0.3) was reacted completely, water 5mL was added, DCM 5mL was extracted twice, the organic phases were combined, saturated sodium bicarbonate (10mL) was washed, saturated brine (10mL) was washed, dried, concentrated, and column chromatography (PE: EA ═ 3:1) gave compound 10, a mass of 0.23g, and a yield of 52.3%.
Mass spectrum of compound 10: (ii) [ M ] ═ 211.0;
nuclear magnetic resonance hydrogen spectrum of compound 10:1H NMR(400MHz,CDCl3)δ8.43(dd,J＝8.2,1.8Hz,1H),8.23(d,J＝1.8Hz,1H),7.91(d,J＝8.2Hz,1H),7.33(d,J＝7.0Hz,1H),6.93(d,J＝7.0Hz,1H)。
example 6
This example prepares an arylthienothiophene-1, 1-dioxide by the reaction where in formula (I) the n ring is pyridine, X is chlorine, R is1、R2Hydrogen, the reaction formula is as follows:
(1) 19.5g of compound 2-chloro-3-pyridinecarboxaldehyde (0.14mol,1.0eq), 28.1g of sodium methanesulfinate (0.28mol,2.0eq), 38.1g of potassium carbonate (0.28mol,2.0eq), 200mL of dimethyl sulfoxide are added into a 250mL three-neck flask, the mixture is stirred for ten minutes under the protection of nitrogen, then the mixture is reacted at 100 ℃ overnight, TLC detection is completed, the temperature is reduced, 800mL of ice water is poured, 300mL of ethyl acetate is extracted for 2 times, organic phases are combined, 100mL of saturated saline is washed for 3 times, dried and subjected to sample mixing column chromatography (petroleum ether: ethyl acetate is 10:1 to petroleum ether: ethyl acetate is 3:1) to obtain 13.5g of colorless oily liquid 11, and the yield is: 52.8 percent.
Mass spectrum of compound 11: [ M +1 ]]+＝186.0；
Nuclear magnetic resonance hydrogen spectrum of compound 11:1H NMR(400MHz,DMSO)δ8.81(dd,J＝4.6,1.2Hz,1H),8.19(dd,J＝7.9,0.7Hz,1H),7.79(dd,J＝7.9,4.6Hz,1H),6.45(s,1H),5.43(s,1H),4.06(dd,J＝13.8,7.2Hz,1H),3.36(dd,J＝13.8,4.7Hz,1H)。
(2) adding 20mL of DCM, 2g of compound 11(10.8mmol,1.0eq) and 5.5g of triethylamine (54.0mmol,5.0eq) into a 100mL three-necked flask, cooling to 10 ℃, slowly adding 2.47g of methanesulfonyl chloride (21.6mmol, 2.0eq, controlling the temperature to be not higher than 10 ℃), reacting for 30min at 0-10 ℃ after finishing dropping, naturally returning to room temperature, reacting for 4h, completing TLC reaction, adding 50mL of water, separating liquid, extracting 20mL of aqueous phase DCM for 2 times, combining organic phases, washing 20mL of saturated sodium bicarbonate for 1 time, drying, and pulping methanol to obtain 1.32g of yellow solid 12 with the yield of 72%.
Mass spectrum of compound 12: [ M +1 ]]+＝168.0；
Nuclear magnetic resonance hydrogen spectrum of compound 12:1H NMR(400MHz,CDCl3)δ8.67(dd,J＝4.9,1.2Hz,1H),7.74(dd,J＝7.7,1.3Hz,1H),7.49(dd,J＝7.7,4.9Hz,1H),7.29(d,J＝7.6Hz,1H),6.85(d,J＝7.6Hz,1H)。
example 7
This example prepares the aromatic Cyclothiophene by the following reaction1, 1-dioxide, wherein in formula (I) n-ring is a benzene ring, X is F, R1Is hydrogen, R2Is methyl, the reaction formula is as follows:
(1) 3g of o-fluorobenzaldehyde (24.2mmol,1.0eq), 5.6g of sodium ethylsulfinate (48.3mol,2.0eq), 1.84g of potassium carbonate (48.3mmol,2.0eq) and 30mL of dimethyl sulfoxide are added into a 100mL three-neck flask, stirred for ten minutes under the protection of nitrogen, then reacted overnight at 100 ℃, TLC (thin layer chromatography) detects the reaction is completed, cooled, poured into 200mL of ice water, extracted for 2 times by 100mL of ethyl acetate, the organic phases are combined, washed for 3 times by 100mL of saturated saline, dried and subjected to column chromatography (petroleum ether: ethyl acetate ═ 10:1 to petroleum ether: ethyl acetate ═ 3:1) to obtain 4.5g of yellow solid 13 with the yield of 94.0%.
Mass spectrum of compound 13: [ M +1 ]]+＝199.0；
Nuclear magnetic resonance hydrogen spectrum of compound 13:1HNMR(400MHz,CDCl3)δ7.78(d,J＝7.7Hz,1H),7.71–7.57(m,3H),5.23(d,J＝5.7Hz,1H),3.64–3.42(m,1H),2.33(s,1H),1.52(d,J＝7.1Hz,3H)。
(2) 1.0g of the product 13(0.006mol, 1eq) and 3.2g of TEA (0.03mol, 5eq) were added to a 50mL single-neck flask containing 10mL of dichloromethane, the temperature was reduced to below 10 ℃, 1.4g of methylsulfonyl chloride (0.012mol, 2eq) was slowly added thereto, after dropping, the mixture was stirred for 30min, TLC (PE: EA: 3:1, Rf: 0.2, Rf: 0.5) was allowed to react, stirring was stopped completely, 8mL of water was added, extraction was carried out by layer, 8mL of DCM was extracted 2 times, the organic phases were combined, saturated sodium bicarbonate (10mL) was washed, saturated brine (10mL) was washed, dried and spin-dried, and column chromatography (PE: EA: 3:1) gave a product 14 of 0.4g mass and a yield of about 44.0%.
Mass spectrum of compound 14: [ M ] ═ 180.0;
nuclear magnetic resonance hydrogen spectrum of compound 14:1H NMR(400MHz,CDCl3)δ7.78(d,J＝7.6,1H),7.65(td,J＝7.6,1.2Hz,1H),7.52(td,J＝7.6,1.2Hz,1H),7.43(d,J＝7.6Hz,1H),7.31(q,J＝1.6Hz,1H),2.28(d,J＝1.6Hz,3H)。
example 8
This example differs from example 1 only in that the reaction temperature in step (1) is 25 ℃, and the remaining reaction conditions are unchanged to produce compound 1. The yield was about 6.7%.
Step (2) is the same as step (2) in example 1.
Example 9
This example differs from example 1 only in that the reaction temperature in step (1) is 280 ℃, and the remaining reaction conditions are unchanged to produce compound 1. The yield was about 48.4%.
Step (2) is the same as step (2) in example 1.
Example 10
This example differs from example 1 only in that the molar ratio of the reaction feeds in step (1) is SM: the ratio of the sodium methanesulfinate to the sodium methanesulfinate is 1:0.3, and the rest reaction conditions are unchanged, so that the compound 1 is prepared. The yield of compound 1 was about 21.6%.
Step (2) is the same as step (2) in example 1.
Example 11
This example differs from example 1 only in that the molar ratio of the reaction feeds in step (1) is SM: the ratio of the sodium methanesulfinate to the sodium methanesulfinate is 1:12, and the rest reaction conditions are unchanged, so that the compound 1 is prepared. The yield of compound 1 was about 89.2%.
Step (2) is the same as step (2) in example 1.
Example 12
This example differs from example 1 only in that the solvent of the reaction was ethanol, the volume was still 130mL, and the remaining reaction conditions were unchanged to produce compound 1. The yield was about 85.6%.
The Applicant states that the present invention is illustrated by the above examples of the process for the preparation of the arylthienothiophene-1, 1-dioxide of the invention, but the invention is not limited to the above detailed process, i.e. it is not intended that the invention necessarily relies on the above detailed process for its implementation. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (24)
1. A method for preparing aromatic benzothiophene-1, 1-dioxide, characterized in that it comprises the following steps: cyclizing an ortho-substituted aromatic ring and sodium alkyl sulfinate in one step, and performing dehydration reaction to obtain aromatic ring bithiophene-1, 1-dioxide;
the ortho-substituted aromatic ring has the structure of a compound shown as a formula I:
wherein n ring is a substituted or unsubstituted aromatic ring, X is a halogen atom, R1Is hydrogen, C1-C20Straight chain alkyl or C3-C20Any one of branched alkyl groups;
the sodium alkylsulfinate has the structure R2CH2SO2Na wherein R2Is hydrogen, C1-C20Straight chain alkyl or C3-C20Any one of branched alkyl groups;
in the one-step cyclization reaction, the molar ratio of the sodium alkylsulfinate to the compound shown in the formula (I) is (1-2) to 1;
the temperature of the one-step cyclization reaction is 100-150 ℃;
in the ortho-substituted aromatic ring, n ring is any one of an unsubstituted or substituted benzene ring, an unsubstituted or substituted pyridine ring, an unsubstituted or substituted pyrimidine ring, an unsubstituted or substituted pyrazine ring, an unsubstituted or substituted pyridazine ring, unsubstituted or substituted thiophene, unsubstituted or substituted furan, unsubstituted or substituted thiazole, unsubstituted or substituted imidazole or unsubstituted or substituted pyrazole;
when the n-ring is a substituted n-ring, the substituent in the n-ring is selected from any one or a combination of at least two of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, trifluoromethyl, nitro, amino, dimethylamino, diethylamino, acetyl, acetamido, acetoxy, methylsulfonamido, ethylsulfonamide, methylsulfonyloxy, ethylsulfonyloxy, carboxyl, methoxycarbonyl, formyl, ethoxycarbonyl, isopropoxycarbonyl, cyano, methylsulfonyl, hydroxyl, trifluoromethoxy, ethoxy, isopropoxy, or n-butoxy.
2. The method of claim 1, wherein X is any one of fluorine, chlorine, bromine, or iodine.
3. The method of claim 1, wherein the one-step cyclization process comprises: under the protection of protective atmosphere, sodium alkylsulfinate and a compound shown as a formula (I) are dispersed in a first reaction solvent to carry out one-step cyclization reaction.
4. The method according to claim 3, characterized in that the gas of the protective atmosphere is selected from nitrogen and/or argon.
5. The method as claimed in claim 1, wherein the temperature of the one-step cyclization reaction is 100-120 ℃.
6. The method according to claim 3, wherein the first reaction solvent is selected from any one of or a combination of at least two of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoramide, methanol, ethanol, isopropanol, acetonitrile and 1, 4-dioxane.
7. The method of claim 6, wherein the first reaction solvent is selected from dimethyl sulfoxide or N, N-dimethylformamide.
8. The process according to claim 3, characterized in that 2-50mL of reaction solvent are charged per 1g of the compound of formula (I) during the one-step cyclization.
9. The process according to claim 8, wherein 5 to 10mL of the reaction solvent is charged per 1g of the compound represented by the formula (I) during the one-step cyclization.
10. The method according to claim 1, wherein the dehydration reaction is carried out by: and mixing the product obtained after the one-step cyclization reaction, methanesulfonyl chloride and alkali in a second reaction solvent, and performing dehydration reaction to obtain the aromatic benzothiophene-1, 1-dioxide.
11. The method as claimed in claim 10, wherein the molar ratio of the product of the one-step cyclization reaction, methanesulfonyl chloride and base is 1 (1-5) to (1-5).
12. The process of claim 11, wherein the molar ratio of the product of the one-step cyclization reaction to the methanesulfonyl chloride and the base is 1:2: 3.
13. The method according to claim 10, wherein the base is selected from any one of sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, sodium methoxide, sodium ethoxide, or potassium tert-butoxide, or a combination of at least two thereof.
14. The process of claim 13, wherein the base is triethylamine.
15. The method according to claim 10, wherein the second reaction solvent is selected from any one of dichloromethane, chloroform, ethyl acetate, isopropyl acetate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1, 4-dioxane, toluene, acetonitrile, acetone, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, N-dimethylformamide, or hexamethylphosphoramide, or a combination of at least two thereof.
16. The process of claim 15, wherein the second reaction solvent is dichloromethane.
17. The method according to claim 10, wherein 5 to 50mL of the second reaction solvent is charged per 1g of the product after the one-step cyclization reaction in the course of the dehydration reaction.
18. The method according to claim 10, wherein the temperature of the dehydration reaction is-20 ℃ to 50 ℃.
19. The method of claim 18, wherein the temperature of the dehydration reaction is between 0 ℃ and 25 ℃.
20. The method of claim 1, comprising the steps of:
(1) under protective atmosphere, dissolving sodium alkylsulfinate and a compound shown as a formula (I) in a molar ratio of (1-2):1 in a reaction solvent, and performing one-step cyclization reaction at 100-150 ℃ to obtain a one-step cyclization reaction solution;
(2) carrying out post-treatment on the one-step cyclization reaction liquid to obtain a product after one-step cyclization reaction;
(3) carrying out dehydration reaction on a product obtained after the one-step cyclization reaction with the molar ratio of 1 (1-5) to (1-5), methanesulfonyl chloride and alkali in a reaction solvent at the temperature of-20-50 ℃ to obtain a dehydration reaction solution;
(4) and carrying out post-treatment on the dehydrated reaction solution to obtain the aromatic benzothiophene-1, 1-dioxide.
21. The method of claim 20, wherein the post-treatment in steps (2) and (4) comprises any one or a combination of at least two of extraction, washing, purification, filtration and drying.
22. The method according to claim 20, wherein the post-treatment in step (2) comprises sequential steps of extraction, washing, drying, concentration and purification to obtain the product after the one-step cyclization reaction.
23. The method according to claim 20, wherein the post-treatment in step (4) comprises sequential extraction, washing, drying and purification to obtain the arylthienothiophene-1, 1-dioxide.
24. The production method according to any one of claims 21 to 23, wherein the purification method comprises any one or a combination of at least two of column chromatography, distillation under reduced pressure, and recrystallization.
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