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b) 2-Methyl-thiazole-5-carboxylic acid To a stirred solution of <strong>[79836-78-5]2-methyl-thiazole-5-carboxylic acid ethyl ester</strong> (1.3 g, 8.0 mmol) in dioxane (12 mL) at room temperature was added NaOH (2N, 12 mL). After 1 h the reaction mixture was neutralized with HCl (IN, 12 mL), then filtered and the collected solid dried in vacuo to give the title compound (758 mg, 70percent) as an off white solid. MS: m/e = 142.0 [M-H]".
41%
With lithium hydroxide monohydrate; water; In tetrahydrofuran; at 20℃; for 16h;
To a stirred solution of compound 97 (41 g, 239.76 mmol) in THF: H2O (7: 1, 400 mL) was added lithium hydroxide monohydrate (29.49 g, 719.29 mmol) at room temperature and stirred for 16 h. The reaction was monitored by TLC. After completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water and acidified with 2 N HCl to pH~2 and extracted using EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford compound 98 (14 g, 41percent) as an off-white solid. TLC: 20percent EtOAc/ hexanes (Rf: 0.1); 1H NMR (DMSO-d6, 400 MHz): delta 13.29 (br.s, 1H), 8.16 (s, 1H), 2.69 (s, 3H); LCMS Calculated for C5H5NO2S: 143.00; Observed: 144.1 (M+1)+.
Ethyl 2-methyl-1,3-thiazole-5-carboxylate [e.g. available from Interchim S.A.] (61 mg) in ethanol (1 ml) was treated with aqueous sodium hydroxide (2M, 0.706 ml). The clear solution was stirred at room temperature for 18 h and then treated with aqueous hydrochloric acid (2M, 0.54 ml). The solution was blown down to dryness and the residual solid dried under vacuum over phosphorus pentoxide. The solid was then suspended in dry dichloromethane (1 ml) and treated at 20° C. with oxalyl chloride (0.032 ml) and DMF (1 drop). The mixture was stirred at room temperature for 30 mins and was then added dropwise to a solution of Intermediate 16 (98 mg) in anhydrous acetonitrile (2 ml). DIPEA (0.064 ml) was added and the solution stirred at room temperature for 20 h. The mixture was diluted with dichloromethane (15 ml), washed with dilute aqueous sodium chloride (2.x.15 ml) and blown down to dryness. The residue was purified by mass directed autoprep HPLC to give a film which was further purified using an SPE cartridge (2 g, aminopropyl) which had been pre-washed with methanol. Elution with methanol gave Example 311 as a white solid (87 mg). LCMS showed MH+=429; TRET=1.94 min.
Synthesis of (E) To a 0° C. solution of <strong>[79836-78-5]ethyl 2-methyl-thiazole-5-carboxylate</strong> (15 g, 88 mmol) in tetrahydrofuran (50 mL) was added aqueous sodium hydroxide solution (5 N, 50 mL) over 10 minutes, and the resulting solution was stirred at room temperature for another 2 hours. It was then acidified with hydrochloric acid (2 N) to pH=1 and extracted with tetrahydrofuran (3*100 mL). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Most of the solvents were removed under reduced pressure and the residue was lyophilized to afford Compound (E) (14 g).
Example 311 N-[1,6-diethyI-4-(tetrahydro-2H-pyran-4-yIamino)-1H- pyrazoIo[3,4-b]pyridin-5-yl]methyl}-2-methyI-1,3-thiazole-5-carboxamideEthyl 2-methyl-1 ,3-thiazole-5-carboxylate [e.g. available from lnterchim S.A.] (61 mg) in ethanol (1ml) was treated with aqueous sodium hydroxide (2M, 0.706ml). The clear solution was stirred at room temperature for 18h and then treated with aqueous hydrochloric acid (2M, 0.54ml). The solution was blown down to dryness and the residual solid dried under vacuum over phosphorus pentoxide. The solid was then suspended in dry dichloromethane (1ml) and treated at 20°C with oxalyl chloride (0.032ml) and DMF (1 drop). The mixture was stirred at room temperature for 30mins and was then added dropwise to a solution of Intermediate 16 (98mg) in anhydrous acetonitrile (2ml). DIPEA (0.064ml) was added and the solution stirred at room temperature for 2Oh. The mixture was diluted with dichloromethane (15ml), washed with dilute aqueous sodium chloride (2 x 15ml) and blown down to dryness. The residue was purified by mass directed autoprep HPLC to give a film which was further purified using an SPE cartridge (2g, aminopropyl) which had been pre-washed with methanol. Elution with methanol gave Example 311 as a white solid (87mg). LCMS showed MH+ =
14 g
With water; sodium hydroxide; In tetrahydrofuran; at 0 - 20℃; for 2.16h;
To a 0° C. solution of <strong>[79836-78-5]ethyl 2-methyl-thiazole-5-carboxylate</strong> (15 g, 88 mmol) in tetrahydrofuran (50 mL) was added aqueous sodium hydroxide solution (5 N, 50 mL) over 10 minutes, and the resulting solution was stirred at room temperature for another 2 hours. It was then acidified with hydrochloric acid (2 N) to pH=1 and extracted with tetrahydrofuran (3*100 mL). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Most of the solvents were removed under reduced pressure and the residue was lyophilized to afford Compound (E) (14 g).
14 g
With water; sodium hydroxide; In tetrahydrofuran; water; at 0 - 20℃; for 2.16667h;
To a 0°C. solution of <strong>[79836-78-5]ethyl 2-methyl-thiazole-5-carboxylate</strong> (15 g, 88 mmol) in tetrahydrofuran (50 ml) was added aqueous sodium hydroxide solution (5 N, 50ml) over 10 minutes, and the resulting solution was stirred at room temperature for another 2 hours. It was then acidified with hydrochloric acid (2 N) to pH=1 and extracted with tetrahydrofuran (3x100 ml). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Most of the solvents were removed under reduced pressure and the residue was lyophilized to afford Compound (E) (14g).
14 g
With water; sodium hydroxide; In tetrahydrofuran; at 0℃; for 2.16667h;
To a 0° C. solution of <strong>[79836-78-5]ethyl 2-methyl-thiazole-5-carboxylate</strong> (15 g, 88 mmol) in tetrahydrofuran (50 mL) was added aqueous sodium hydroxide solution (5 N, 50 mL) over 10 minutes, and the resulting solution was stirred at room temperature for another 2 hours. It was then acidified with hydrochloric acid (2 N) to pH=1 and extracted with tetrahydrofuran (3×100 mL). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Most of the solvents were removed under reduced pressure and the residue was lyophilized to afford Compound (E) (14 g).
With hydrazine; In ethanol; for 12h;Heating / reflux;
Preparation 9: 2-methyl-1,3-thiazole-5-carbohydrazide; EPO <DP n="44"/>The title compound was prepared in analogy to the method described in Preparation 4 starting from ethyl 2-methyl-1 ,3-thiazole-5-carboxylate (0.5g) and used without further purification. Ethanol was used instead of methanol. MS (mlz): 158.1 [MH]+.
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