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i) Thiazole-2-carboxylic acid (1.60 g, 12.4 mmol) was added to a solution of lithium diisopropylamine (1 M in THF/heptane/ethylbenzene, 26 mmol, 26 mL) in dry THE (100 mL) at -78 C and the RM was stirred for 30 mi Tetrabromomethane (4.52 g, 13.6 mmol) was added and the RM was stirred for 2 h. The reactionRM was quenched by adding water (30 mL). The RM was allowed to reach RT and diluted by adding an aqueous saturated solution of NaHCO3 (50 mL). The RM was filtered through a pad of celite and extracted with EtOAc (50 mL). The organic layer was discarded and the aqueous layer acidified using a 1 N solution of HCI until pH 3-4. The solution was then extracted with EtOAc (3x 30 mL). The combined organic layer was dried over Na2SO4 and concentrated in vacuo to leave INT-18A (0.420 g, 2.02 mmol,16%). LCMS: caic. for [M+H]*=207.90, found 208.0.
16%
Thiazole-2-carboxylic acid (1.60 g, 12.4 mmol) was added to a solution of LDA (1 M in THF/heptane/ethylbenzene, 26.0 mmol, 26 mL) in dry THE (100 mL) at-78 C and the mixture was stirred for 30 mm.CBr4 (4.52 g, 13.6 mmol) was added and the reaction was stirred for 2 h. The RM was quenched by adding water (30 mL). The mixture was allowed to reach rt and diluted by adding an aqueous saturated solution of NaHCO3 (50 mL). The mixture was filtered through a pad of Celite and extracted with EtOAC (50 mL). The organic layer was discarded and the aqueous layer acidified using a 1 M solution of HCIuntil pH acidic. The solution was then extracted with EtOAc (3x 30 mL). The combined organic layer was dried over Na2SO4 and concentrated in vacuo to leave 5-bromo<strong>[14190-59-1]thiazole-2-carboxylic acid</strong> (0.42 g, 2.0 mmol, 16%). LCMS: cal for [M+H] = 207.90, fd 208.0.
tert-butyl ((trans)-3-(5-bromothiazole-2-carboxamido)cyclobutyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere;
Into a 100 mL round-bottom flask was placed 5-bromothiazole-2-carboxylic acid (300 mg, 1.41 mmol), N,N-dimethylformamide (5 mL), tert-butyl N-[(trans)-3- aminocyclobutyl]carbamate (270 mg, 1.42 mmol), N,N-diisopropylethylamine (560 mg, 4.33 mmol) and HATU (661 mg, 1.74 mmol). The resulting solution was stirred for 1 h at room temperature. The reaction mixture was poured into water (5 mL) and then extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by prep-TLC (eluting with 1 : 1 ethyl acetate/petroleum ether) to afford tert-butyl ((trans)-3-(5-bromothiazole-2- carboxamido)cyclobutyl)carbamate as a yellow solid. LC-MS (ESI) m/z 320.0, 322.0 [M+H-tBu]+
tert-butyl (S)-3-((5-bromothiazole-2-carboxamido)methyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
513 mg
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; for 1h;
To the solution of 5-bromothiazole-2-carboxylic acid (scheme 8-33 compound S1, 458 mg, 2.2mmol) and <strong>[140645-24-5]tert-butyl (S)-3-(aminomethyl)piperidine-1-carboxylate</strong> (scheme 8-33 compound S2, 429 mg, 2.0mmol) in DCM (15.0 mL) at 0 C, HATU (912 mg, 2.4mmol) was added, followed by addition of DIEA (3.6mmol). The mixture was stirred for 1 h. The volatiles were evaporated under reduced pressure. The residue was diluted with ethyl acetate (60mL) and washed with saturated NaHCO3, water and brine. The organic solution was dried over MgSO4. The solution was filtered and the filtrate was concentrated. The remaining material was purified to afford 513 mg of title product. LC (method A): tR = 2.30 min. LC/MS (EI) m/z: [M + H]+ 404.06, 406.09.
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