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Stage #1: at 0 - 20℃; Stage #2: With hydrogenchloride In water at 0℃;
[0207] The title compound was synthesized according to a procedure published by Huddleston and Barker, Synth. Commun., 1979, 9, 8, 731-734, which is hereby incorporated by reference in its entirety. To a solution of 15 mL dry MeOH was added sodium (700 mg; 30 mmol) to give a 2M solution of NaOMe. Methyl thioglycolate (1.9 g; 18 mmol) was added. The solution was cooled to O0C and methyl 2-chloroacrylate (2.1 g; 17.4 mmol) was added drop wise. Stirring was continued overnight raising the temperature to room temperature. The mixture was re-cooled to 0°C and the quenched by addition of HCl (4M aq, ~5mL). Water was added and extraction done with 2 times EtOAc. The combined organic phases were dried over Na2SO4, filtered and the solvent removed in vacuo to give 2.0 g (70 percent) of a brown oil that solidified upon drying. Used without further purification.[0208] LCMS m/z -, tR = 4.12 min, purity (UV/MS) 98/20. GCMS m/z 158 (M), *R = 4.52 min. 1H NMR (CDCl3, 400 MHz) δ 9.56 (br s, IH, OH), 7.37 (d, IH, J = 5.2 Hz, thiopheneH), 6.74 (d, IH, J= 5.2 Hz, thiopheneH), 3.89 (s, 3H, OMe).
64%
With sodium In methanol at 0 - 20℃; for 2 h;
To dry methanol (81 mL), under nitrogen, was added sodium metal (3.68 g, 304 mmol). After H2 evolution ceased, the solution was cooled to 0° C. and methyl thioglycolate (10 g, 179 mmol) was added dropwise. A solution of methyl-2-chloroacrylate (10.88 g, 179 mmol) in methanol (21 mL) was then added slowly, resulting in the formation of yellow precipitate. The solution was allowed to warm to ambient temperature and stirred for 2 h. The solvent was removed in vacuo to give a dark yellow solid that was acidified to pH 2 with 4 N HCl. The resulting aqueous solution was extracted with dichloromethane (3.x.150 mL) and the combined organic solutions were washed with water (3.x.150 mL), dried over MgSO4, filtered, and concentrated to give a dark oil. The oil was subjected to column chromatography on silica gel (20:1 hexanes/ethyl acetate) to give (12) (18.4 g) as a crystalline solid in 64percent yield. TLC (20:1 hexanes/ethyl acetate) Rf 0.47; 1H NMR (CDCl3) δ 9.58 (s, 1H), 7.59 (d, J=5.7 Hz, 1H), 6.75 (d, J=4.8 Hz, 1H), 3.90 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.8, 164.7, 131.7, 119.4, 52.2; EI-MS m/e 158.0039 (M+ calculated 158.0038 for C6H6O3S).
With sodium hydrogencarbonate In methanol at 10℃; Reflux
To a suspension of 38.4 g of NaHCO3 in 100 mL of methanol at 10 °C was slowly added a mixture of 10 mL of methyl thioglycolate (102 mmol) and 12.2 mL of methyl 2,3-dichloropropionate (102 mmol) in 20 mL of methanol. The mixture was refluxed for 15 h. After cooling at room temperature, the solution was acidified to pH = 1 with HCl 2M and extracted with ether. The organic phase was washed with water then dried over anhydrous MgSO4 and the solvent was removed at reduced pressure. The crude product was purified by flash chromatography on silica gel (CH2Cl2 - EP : 1/1) to afford 8.9 g of 1 (55 percent). White solid mp = 43 °C 1H NMR (CDCl3): 3.90 (s, 3H), 6.75 (d, 1H, J = 5.2 Hz), 7.59 (d, 1H, J = 5.2 Hz), 9.58 (s, 1H). MS (EI) : m/z = 158 (M+.)
Stage #1: at 20℃; for 1 h; Cooling with ice Stage #2: at -10 - 45℃; for 17 h;
Methyl 2-mercaptoacetate (4.31 mL, 47.1 mmol) was added to MeOH (94 mL) and cooled in an ice bath. Following, sodium hydride (3.39 g, 85 mmol) was slowly added and the reaction was stirred for 1 hour at room temperature. The reaction was cooled to -10 C and ethyl propiolate (5.01 mL, 48.0 mmol) was slowly added. The reaction was stirred at 0 °C for 1 hour, room temperature for 1 hour, and heated to 45 °C for three hours. (0342) Following, the reaction was heated for 12 hours at 35 °C. All reaction solvent was evaporated and the reaction was redissolved in water, neutralized to pH 7, and extracted 10 times with 3: 1 chloroform/IPA. The organic extracts were combined, evaporated, and dissolved in EtOAc. The EtOAc/reaction mixture was filtered through a pad of silica and washed with EtOAc. The organic was collected and condensed to generate methyl 3- hydroxythiophene-2-carboxylate (3.66 g, 49.1percent).
With sodium In methanol at 0 - 26℃; for 2 h; Inert atmosphere; Cooling with ice
A thermometer and a dropping funnel were placed on a 250-ml two-necked flask and cooled with ice water (_10 ° C to 0 ° C). 30 ml of anhydrous methanol and 0. 8 g of metallic sodium cut into small pieces were placed in a flask and sealed with nitrogen.[0144] When the internal temperature reached 0 & lt; 0 & gt; C, a solution of 2.4 g of methyl 2-methylsulfate, completely dissolved in 20 ml of methanol2-mercaptoacetate, Sigma-Aldrich, USA) was slowly added dropwise to a dropping funnel.[0145] After completion of the dropwise addition, a solution of 3.5 g of ethyl 2-chloropropanoate2-chloroacrylate, Sigma-Aldrich, U.S.A.) was slowly added dropwise to a dropping funnel.After completion of the dropwise addition, the cooling water was removed and stirred at room temperature (18 ° C to 26 ° C) for 2 hours. At this point a yellow solid formed.[0147] The methanol in the stirred product was concentrated, acidified to pH 2 with 4N hydrochloric acid. The acidified reaction product was diluted with methylene chloride, extracted three times with 30 ml each, and the organic solvent layer was collected and washed three times. The organic solvent layer was separated,Dried over anhydrous magnesium sulfate, and allowed to stand for 20 minutes. Thereafter, the anhydrous magnesium sulfate was removed by filtration, and then the organic solvent was removed from the residue by a rotary concentrator for concentration. To give the product as a yellow oil. The oily product obtained by this method was crystallized in a mixture of n-hexane and ethyl acetate (n-hexane: ethyl acetate = 20: 1) to give pale yellow crystals. The yield was 68percent.
Reference：
[1] Patent: CN106146455, 2016, A, . Location in patent: Paragraph 0139; 0140; 0141; 0142; 0143; 0144-0147
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[ 2365-48-2 ]
[ 623-47-2 ]
[ 5118-06-9 ]
Reference：
[1] Patent: EP510473, 1992, A1,
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[ 2689-69-2 ]
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Reference：
[1] Journal of Organic Chemistry, 1980, vol. 45, # 4, p. 617 - 620
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[ 2365-48-2 ]
[ 922-67-8 ]
[ 5118-06-9 ]
Reference：
[1] Chemische Berichte, 1954, vol. 87, p. 848,855
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[ 115777-72-5 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 3, p. 419 - 425
To a solution of 10g of 1 (63.2 mmol) in 22 mL of acetic acid was added 3.24 mL of bromine (63.2 mmol) then the mixture was stirred at room temperature for 24h. The solution was poured on 50 mL of water and extracted with 50 mL of CH2Cl2. The organic phase was washed twice with 50 ml of water then dried over MgSO4 and the solvent was removed at reduced pressure. The crude product was purified by flash chromatography on silica gel (CH2Cl2 - EP : 1/2) to afford 11.3 g of 2 (76 percent). m.p. = 86 °C 1H NMR (CDCl3): 3.92 (s, 3H), 7.38 (s, 1H), 9.74 (s, 1H) 13C NMR (CDCl3): 52.2, 102.6, 103.8, 128.1, 160.4, 165.8. MS (EI) : m/z = 236 (M+.)
10%
With N-Bromosuccinimide In tetrahydrofuran; methanol at 0 - 20℃; for 6 h;
General procedure: NBS (63 mg,0.35 mmol) was added to a solution of 1 (100 mg, 0.70 mmol) in 10 mL of THF – CH3OH (1:1, v/v) at 0 C and the mixture was stirred at roomtemperature. After 2 h, NBS (50.4 mg, 0.28 mmol) was added again to the mixture at 0 C, and it was stirred at room temperature for 2 h. The solvent wasremoved in vacuo, and water (15 mL) was added to the residue. The aqueouslayer was extracted three times with EtOAc (30 mL). The organic layers weregathered together, washed with water and brine, dried over MgSO4, filtered,and concentrated in vacuo. Et2O (10 mL) was added to the dry residue todiscard succinimide. The filtrate was concentrated in vacuo, and heptane(10 mL) was added to the dry residue to afford 4 as an orange powder (68.6 mg,44percent yield).
With sodium hydroxide; potassium carbonate; In acetone;
3-Methoxy-2-thiophene carboxylic acid (VI: R'=CH3) 48.5 g (0.31 mmoles) of 3-hydroxy-2-thiophene carboxylic acid methyl ester (IV: R3 =H) are dissolved in 400 ml of acetone, 84.7 g (0.61 moles) of potassium carbonate, 77.3 g (0.61 moles) of dimethylsulfate are added, and the mixture is refluxed with stirring for 1 hour. The salt mass is aspirated, washed several times with acetone and the combined filtrate is concentrated in vacuo. 750 ml of aqueous 2N sodium hydroxide are added and boiled. The reaction solution is cooled, washed with ether and acidified with concentrated HCl. The precipitating colorless crystals are aspirated and recrystallized from ethanol. Yield: 43.1 g (89%), m.p. 184-185 C.
A thermometer and a cooler were placed on a 250-ml three-necked flask. At room temperature (18 C to 25 C), 1.38 g<strong>[5118-06-9]Methyl 3-hydroxythiophene-2-carboxylate</strong> was dissolved inIn 20 ml of dimethylformamide.[0153] 1.2 g of K2C03 was placed in the lysate and stirred at room temperature (18 C to 25 C) for 10 minutes. StirringWhen the solid K2C03.[0154] After the oil bath was set, stirring was carried out at 40 C for 30 minutes. After that, 1.4 g of methyl 2-bromoacetate was added in one portion(Methyl 2-bromoacetate), the temperature rose to 90 C after stirring. After reacting for about 2 hours, water was added to the flask to obtain a white solid.The reaction was confirmed to be complete by TLC and extracted three times with dichloromethane, and the organic solvent layer was collected every 50 ml. The organic solvent layer was washed with water three times, each time with 50 ml. The organic solvent layer was separated, placed in anhydrous magnesium sulfate, and left to stand for 20 minutes to dry. Then, the anhydrous magnesium sulfate was removed by filtration, and then the organic solvent was removed from the residue by a rotary concentrator for concentration.To thereby obtain 2.3 g of methyl 3- (2-methoxy-2-oxoethoxy) thiophene-2-carboxylate3- (2-methoxy-2-oxoethoxy) thiophene-2-carboxylate) in 87% yield.
[0209] 3-Hydroxy-2-methoxycarbonylthiophene (2.0 g; 12.6 mmol) was dissolved in 10 mL dry DMF and sodium hydride (~60% in mineral oil, 610 mg; ~15.2 mmol) was added portion wise. After hydrogen evolution had ceased the mixture was cooled to 5 C and diethylthiocarbamoyl chloride (2.48 g; 16.4 mmol) was added in one <n="72"/>portion and the temperature was raised to 80 0C for 1 hour. After cooling to room temperature the mixture was poured into a 1% aqueous potassium hydroxide solution (25 mL). The aqueous phase was extracted with toluene (3 times 15 mL). The combined organic phases were washed with 5% aqueous HCl (10 mL), water (10 mL) before drying over Na2SO4. After filtration the solvent was removed by evaporation to give a crude brown oil that was purified by silica gel column chromatography (20 % EtOAc in heptane, R/= 0.45) to give the title compound as a brown oil (1.74 g; 51 %)[0210] LCMS m/z 274 [M+l]+, tR = 3.98 min, purity (UV/MS): 80/70. GCMS m/z 273, tR = 7.54 min. 1H NMR (CDCl3, 400 MHz) delta 7.44 d, IH, J = 5.6 Hz, thiopheneH), 6.93 (d, IH, J= 5.6 Hz, thiopheneH), 3.88 (q, 2H, J= 7.2 Hz, CH2), 3.82 (s, 3H, OMe), 3.74 (q, 2H, J = 7.2 Hz, CH2), 1.35 (t, 3H, J = 7.2 Hz, Me), 1.33 (t, 3H, J = 7.2 Hz, Me).
Example 1; (a) 3-Hydroxy-thiophene-2-carboxylic acid amide (2); To a screw tight 150ml pressure vessel was added <strong>[5118-06-9]3-hydroxy-thiophene-2-carboxylic acid methyl ester</strong> (1)(5.0g, 31.8mmol) and ammonia in methanol (7N, 80ml). The pressure vessel was sealed and contents stirred for 48 hours at 6O0C. The reaction was cooled to room temperature and the solution evapourated to dryness to afford white crystalline solid (2). Single peak in LC-MS (4.9g, 100% yield); m/z (LC-MS, ESP), RT=2.96mins, (M+H) 144.
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