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PREPARATION 5 Methyl 3-hydroxy-5-methylthiophene-2-carboxylate To a stirred suspension of 2-chloro-2-methoxycarbonylthiophen-3(2H)-one (6.35 g, 33 mmol) in acetic acid (20 ml) was added sulphuric acid (1.8 ml) in acetic acid (20 ml). The mixture was stirred until dissolved then methyl mercaptan was bubbled through for 0.5 hours (total approximately 2 g). The mixture was stirred at room temperature for 18 hours, poured onto ice-water and the oily precipitate extracted into dichloromethane. After evaporation of solvent the crude oil was used in the following preparation.
EXAMPLE 3 Methyl 3-hydroxy-5-methyl-2-thiophenecarboxylate Prepared by the method described in Example 1 from ethyl acetoacetate (130 g, 1.0 mole), methyl thioglycolate (212 g, 2.0 moles) and sodium (53 g, 2.3 moles). The crude product is shaken with two portions of dichloromethane, filtered, and the filtrate stripped of solvent under reduced pressure to afford the product (90.1 g); mp 50-53 C.
With sodium;
EXAMPLE 3 Methyl 3-hydroxy-5-methyl-2-thiophenecarboxylate. Prepared by the method described in Example 1 from ethyl acetoacetate (130 g, 1.0 mole), methyl thioglycolate (212 g, 2.0 moles) and sodium (53 g, 2.3 moles). The crude product is shaken with two portions of dichloromethane, filtered, and the filtrate stripped of solvent under reduced pressure to afford the product (90.1 g); mp 50-53C.
EXAMPLE 21 Methyl 3-(1-methylethoxy)-5-methyl-2-thiophenecarboxylate Methyl 3-hydroxy-5-methyl-2-thiophenecarboxylate (20.0 g, 116 mmoles) is dissolved in acetonitrile (450 mL) under argon. Triisopropylisourea (86.6 g, 465 mmoles) is added and the mixture stirred and heated under reflux. After 24 hours the mixture is cooled and the precipitate filtered off, rinsed with cold MeCN and discarded. The filtrate is stripped of solvent by rotary evaporator, then the excess triisopropylisourea is removed by distillation under reduced pressure. The remaining residue is dissolved in a small amount of ethyl acetate, cooled, filtered, and passed through a short column of silica gel. Evaporation of the effluent under reduced pressure leaves the product as an oil (18.8 g) sufficiently pure for further use.
In acetonitrile;
EXAMPLE 21 Methyl 3-(1-methylethoxy)-5-methyl-2-thiophenecarboxylate. Methyl 3-hydroxy-5-methyl-2-thiophenecarboxylate (20.0 g, 116 mmoles) is dissolved in acetonitrile (450 mL) under argon. Triisopropylisourea (86.6 g, 465 mmoles) is added and the mixture stirred and heated under reflux. After 24 hours the mixture is cooled and the precipitate filtered off, rinsed with cold MeCN and discarded. The filtrate is stripped of solvent by rotary evaporator, then the excess triisopropylisourea is removed by distillation under reduced pressure. The remaining residue is dissolved in a small amount of ethyl acetate, cooled, filtered, and passed through a short column of silica gel. Evaporation of the effluent under reduced pressure leaves the product as an oil (18.8 g) sufficiently pure for further use.
With bromine; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; acetic acid;
EXAMPLE 4 Methyl 4-bromo-3-hydroxy-5-methyl-2-thiophenecarboxylate Bromine (4.6 g, 29 mmoles) is added dropwise at room temperature to a stirred solution of <strong>[5556-22-9]methyl 3-hydroxy-5-methyl-2-thiophenecarboxylate</strong> (5.0 g, 29 mmoles) in acetic acid (25 mL). After 16 hours the mixture is stirred into ice water (200 ml), and the precipitate is filtered off, rinsed with water, with 5% aqueous sodium thiosulfate, again with water and dried. Recrystallization from methyl t-butyl ether gave the pure product (4.1 g); mp 96-97 C.
With bromine; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; acetic acid;
EXAMPLE 4 Methyl 4-bromo-3-hydroxy-5-methyl-2-thiophenecarboxylate. Bromine (4.6 g, 29 mmoles) is added dropwise at room temperature to a stirred solution of <strong>[5556-22-9]methyl 3-hydroxy-5-methyl-2-thiophenecarboxylate</strong> (5.0 g, 29 mmoles) in acetic acid (25 mL). After 16 hours the mixture is stirred into ice water (200 mL), and the precipitate is filtered off, rinsed with water, with 5% aqueous sodium thiosulfate, again with water and dried. Recrystallization from methyl t-butyl ether gave the pure product (4.1 g); mp 96-97C.
2-carbomethoxy-3-(diethoxythiophosphoryloxy)-5-methyl-thiophene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N-methyl-acetamide; mineral oil;
EXAMPLE 10 2-carbomethoxy-3-(diethoxythiophosphoryloxy)-5-methyl-thiophene 4.7 g of a 60% suspension of sodium hydride in mineral oil were slowly added to a solution of 20 g of <strong>[5556-22-9]2-methoxycarbonyl-3-hydroxy-5-methyl-thiophene</strong> in 200 ml of dimethylformamide and after stirring the mixture for 1 hour at 20 C., a solution of 22.4 g of O,O-diethyl-chlorothiophosphate in 50 ml of dimethylformamide was rapidly added thereto. The mixture was stirred for 15 hours at 20 C. and the resulting suspension was poured over a mixture of ice and water. The mixture was extracted with ether and the extracts were dried and concentrated to dryness. The residue was chromatographed over silica gel and elution with a 9-1 cyclohexane-ethyl acetate mixture gave 11.5 g of 2-carbomethoxy-3-(diethoxy-thiophosphoryloxy)-5-methyl-thiophene with a refractive index of nD22 = 1.5272. Analysis: C11 H17 O5 PS2. Calculated: %C, 40.74; %H, 5.19; %P, 9.55. Found: %C, 40.7, %H, 5.4; %P, 9.0.
3-hydroxy-5-methyl-dihydrothiophene-2-carboxylic acid methyl ester[ No CAS ]
[ 5556-22-9 ]
Yield
Reaction Conditions
Operation in experiment
With sulfuryl dichloride; In dichloromethane;
(b) (Reaction): 3-hydroxy-5-methylthiophene-2-carboxylic acid methyl ester STR65 17.4 Parts of 3-hydroxy-5-methyldihydrothiophene-2-carboxylic acid methyl ester are dissolved in 100 parts by volume of methylene chloride. 14.9 parts of sulfuryl chloride in 20 parts by volume of methylene chloride are added in the course of 30 minutes at 10 C., whilst passing nitrogen into the mixture. The mixture is then distilled. 12.9 parts (75% of theory) of 3-hydroxy-5-methylthiophene-2-carboxylic acid methyl ester of boiling point 67-70 C./0.3 mbar are obtained.
methyl 5-methyl-3-(((trifluoromethyl)sulfonyl)oxy)thiophene-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With pyridine; In dichloromethane; for 2.0h;
Step 1: methyl 5-methyl-3-(((trifluoromethyl)sulfonyl)oxy)thiophene-2-carboxylate Into a 100-mL round-bottom flask, was placed <strong>[5556-22-9]methyl 3-hydroxy-5-methylthiophene-2-carboxylate</strong> (1.04 g, 5.74 mmol), dichloromethane (7 mL), pyridine (1.44 mL, 17.81 mmol). This was followed by the addition of Tf2O (1.45 mL, 8.61 mmol) dropwise with stirring at 0 C. The resulting solution was stirred for 2.0 h at 0 C. in a water/ice bath. The reaction progress was monitored by GCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3*15 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2*20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:9). This resulted in 1.74 g (99%) of methyl 5-methyl-3-(((trifluoro methyl)sulfonyl)oxy)thiophene-2-carboxylate as yellow oil.
99%
With pyridine; In dichloromethane; for 2.0h;
Into a 100-mL round-bottom flask, was placed <strong>[5556-22-9]methyl 3-hydroxy-5-methylthiophene-2-carboxylate</strong> (1.04 g, 5.74 mmol), dichloromethane (7 mL), pyridine (1.44 mL, 17.81 mmol). This was followed by the addition of Tf2O (1.45 mL, 8.61 mmol) dropwise with stirring at 0 C. The resulting solution was stirred for 2.0 h at 0 C. in a water/ice bath. The reaction progress was monitored by GCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3*15 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2*20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:9). This resulted in 1.74 g (99%) of methyl 5-methyl-3-(((trifluoro methyl)sulfonyl)oxy)thiophene-2-carboxylate as yellow oil.
99%
With pyridine; In dichloromethane; for 2.0h;
Into a 100-mL round-bottom flask, was placed methyl 3-hydroxy-5- methylthiophene-2-carboxylate (1.04 g, 5.74 mmol), dichloromethane (7 mL), pyridine (1.44 mL, 17.81 mmol). This was followed by the addition of Tf20 (1.45 mL, 8.61 mmol) dropwise with stirring at 0C. The resulting solution was stirred for 2.0 h at 0C in a water/ice bath. The reaction progress was monitored by GCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3x15 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2x20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :9). This resulted in 1.74 g (99%) of methyl 5-methyl-3-(((trifluoro methyl)sulfonyl)oxy)thiophene-2-carboxylate as yellow oil.
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