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With sodium hydroxide; In tetrahydrofuran; methanol; water; at 20℃; for 24h;
[0405] A stirred solution of ethyl-2-tert-butoxycarbonyloxyamino-4-methyl-thiazole-5-carboxylate (1.1 g, 4.2 mmol) in tetrahydrofuran-methanol (80 mL, 1:1) was treated with a 6N aq. NaOH solution (20 mL, 120 mmol). The mixture was stirred at rt for 24 h. Most of THF and methanol were removed by distillation under reduced pressure and the aq. Solution was acidified with 6 N aq. HCl solution (22 mL). The precipitated solid was filtered, washed with water and ether, air dried followed by drying in vacuo to obtain the title acid (940 mg, 96%) as an off-white solid.
With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 1h;
To an cooled (0 C) dichloromethane (4 mL) solution of 2-[(tert- butoxycarbonyl)amino]-l,3-thiazole-5-carboxylic acid (0.30 g) was added a solution of oxalyl chloride (0.13 mL) in dichloromethane (1 mL). One drop of N,N- dimethylformamide was added and the mixture stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue dissolved in acetonitrile (5 mL). To the cooled (0 C) acetonitrile solution, a 2 M solution of (trimethylsilyl)diazomethane in tiexanes (1.23 mL) was added and the mixture stirred at 0 C for 1 hour. To the reaction mixture, a solution of 33 wt. % hydrogen bromide in acetic acid (0.20 mL) was added and the mixture stirred at 0 C for a further 20 minutes. A saturated aqueous solution of sodium hydrogen carbonate ( 0 mL) was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated to give the crude title compound having the following physical properties (0.37 g). LC MS fR 1.92 minutes; MS (ES+) m/z 265 and 267 (M-C(CH3)3+H) a.
With oxalyl dichloride; In dichloromethane;
[00106] Compound 8 was made using by adapfing the synthesisdsdosed n J.Med.Chem. 2006, 6819. Synthesis of amde 5 was accomphshedn two steps, starting from compound 1. Compound I was converted to acidchorde 2 using oxay chorde n dchoromethane (DCM). Formafion of theacd chorde was confirmed by quenching an aquot n methano (MeOH);LCMS anayss ndcated the presence of the corresponding methy? ester 3 n>90%. Add Won of 2 to a mixture of excess anWne 4 and dsopropy ethyamne(DPEA) gave good conversion to amine 5. After fHtehng the sohds off thisafforded 1.15 g (40%) amde 5 n high purIty. Remova of the Boc-group using tr[fluoroacefic acid (TFA) gave good conversion to amine 6. Amine 6 was converted to compound 8 n the presence of compound 7 and sodium t-butoxde (NaOBu-t).
With thionyl chloride; N,N-dimethyl-formamide; In tetrahydrofuran; dichloromethane; at 25 - 30℃;
Into a clean and dry 1 L 4-neck round bottom flask connected to a mechanical stirrer, condenser, thermometer socket is charged with 2-tert-butoxy-carbonylaminothiazole-5-carboxylic acid (3) (25.0 g), THF (1 L) and DMF (1 mL) at 25-30 C under stirring. Charged thionyl chloride (22.5 mL of thionyl chloride dissolved in 125 mL of dichloromethane) to the mass at 25-30 C. Maintained the reaction mass at 25-30 C for 4-6 h and after TLC compliance, distilled-off solvent completely under plant vacuum at the temperature not crossing 50 C. Charged THF (125 mL) to the reaction mass, stirring the mass for 10-15 min and distilled-off solvent completely under plant vacuum at the temperature not crossing 40 C. Charged 125 mL of dichloromethane to the reaction mass, stirring the mass for 10-15 min and distilled-off solvent completely under plant vacuum at the temperature not crossing 40 C to furnish 27-28 g of crude compound.
With thionyl chloride; In tetrahydrofuran; dichloromethane; N,N-dimethyl-formamide; at 25 - 30℃;
Into a clean and dry 1.0. L 4-neck RB charged 2- tert-butoxycarbonylamino- thiazole-5-carboxylic acid(25gm),and THF(lltr, Lot-I) and DMF(10 ml) at (0075) temperature 25-30C under stirring. Charged thionyl chloride (22.5 ml, dissolved (0076) in 125ml of dichloromethane-Lot-I) to the mass at temperature 25-30C, (0077) maintained the mass at temperature 25-30C for 4-6hrs., after completion of the (0078) reaction, distilled-off solvent completely under plant vacuum at temperature not (0079) crossing 50C, charged THF (125ml, Lot-II) to reaction mass.Stirr the mass for (0080) 10-15 min. Distilled-off solvent completely under plant vacuum at temperature not crossing 40C, charged dichloromethane (125ml, Lot-II) to reaction mass. (0081) Stirred the mass for 10-15 min.Distilled-off solvent completely under plant (0082) vacuum at temperature not crossing 40C. Distilled-off solvent completely under (0083) plant vacuum at temperature not crossing 60C. Crude acid chloride is directly (0084) taken to next stage in-situ. (0085) Weight: 27 gm
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