2-BROMO-THIAZOLE-5-CARBOXAMIDE

A mixture of (S)-3-(1-aminoethyl)-6-chloroquino- lin-2(1H)-one HC1, 11-1 (450 mg, 1.7 mmol, 1 eq.), 2-bro- mothiazole-5-carboxamide (425 mg, 2.05 mmol, 1.2 eq.) and DIEA (482 mg, 3.7 mmol, 2.2 eq.) in 10 mE DM50 in a sealed tube was heated at 140 C. for 2.5 hours. The reaction was then poured into water and extracted with EtOAc (x2). The combined organic extracts were washed with brine and dried over Na2SO4. After rotary evaporation, trituration with DCM afforded 184 mg crude product as a solid. Chromatography over 6.5 g silica gel, eluting with a 0 to 15% EtOH/DCM gradient, provided 100 mg of crude product as a gold solid still containing DIEA. Trituration with DCM, followed by evaporation of a MeOR solution of the solid afforded 70 mg 1-10 as a yellow-orange solid (10%). H-NMR (300 MHz, d6DMSO) oe ppm: 12.0 (s, 0.75H), 8.54 (d, J=6.87, 1H), 7.79 (d, J=2.19, 1H), 7.73 (s, 1H), 7.61 (s, 1H), 7.61 (broad s, 1H), 7.48 (dd, J=2.19, 8.79, 1H), 7.29 (d, J=8.79, 1H), 7.06 (broad s, 1H), 4.89 (m, 1H), 1.40 (d, J=6.60, 3H). ECMS (Method 3): Rt 3.85 mi mlz349 [M+H]Into a 2 L round-bottom flask was added ethyl 2- bromothiazole-5-carboxylate (50.0 g, 212 mmol), THF (500 niL) and MeOH (250 mL). To this was added concentrated ammonium hydroxide in water (590 mL) and the reaction mixture was stirred at room temperature for 4 h. The solvents were removed under reduced pressure, and the crude mixture poured into a separatory funnel containing brine (1 L). The aqueous layer was extracted with EtOAc (4 x 500 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound.Step 2: 2-Bromo- 1 , 3-thiazole-5-carbonitrile; Into a 2 L round-bottom flask containing 2-bromo-l, 3-thiazole-5-carboxamide (41.5 g, 201 mmol) in CH2Cl2 (1.3 L) was added triethylamine (70 mL, 502 mmol). The resulting solution was cooled to 0 0C and TFAA (34 mL, 241 mmol) was added slowly over 15 min. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was poured into a 3 L separatory funnel containing saturated aqueous NaHCO3 solution (500 mL). The aqueous layer was extracted with CH2Cl2 (2 x 1.2 L) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was filtered through a short plug of silica gel on a sintered glass funnel, washing with copious quantities of EtOAc. The filtrate was concentrated under reduced pressure to provide the title compound.Into a 2 L round-bottom flask containing 2-bromo- l, 3-thiazole-5-carboxamide (41.5 g, 201 mmol) in CH2Cl2 (1.3 L) was added triethylamine (70 mL, 502 mmol). The resulting solution was cooled to 0 C and trifluoroacetic anhydride (34 mL, 241 mmol) was added slowly over 15 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was poured into a 3 L separatory funnel containing saturated aqueous NaHCO3 solution (500 mL). The aqueous layer was extracted with dichloromethane (2 x 1.2 L) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude reaction mixture was filtered through a short plug of silica gel on a sintered glass funnel, washing with copious quantities of EtOAc. The filtrate was concentrated under reduced pressure to provide the title compound.Step 2 2-Bromo- 1 , 3-thiazole-5-carbonit'le; Into a 2 L round-bottom flask containing 2-bromo-l, 3-thiazole-5-carboxamide (41 5 g, 201 mmol) in CH2Cl2 (1 3 L) was added t'ethylamme (70 mL, 502 mmol) The15 resulting solution was cooled to 0 0C and TFAA (34 mL, 241 mmol) was added slowly over 15 mm The reaction mixture was allowed to warm to room temperature and stirred for 2 h The reaction mixture was poured into a 3 L separatory funnel containing saturated aqueous NaHCO3 solution (500 mL) The aqueous layer was extracted with CH2Cl2 (2 x 1 2 L) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under20 reduced pressure The crude reaction mixture was filtered through a short plug of silica gel on a sintered glass funnel, washing with copious quantities of EtOAc The filtrate was concentrated under reduced pressure to provide the title compoundInto a 2 L round-bottom flask containing 2- bromo-l, 3-thiazole-5-carboxamide (41.5 g, 201 mmol) in CH2Cl2 (1.3 L) was addedtriethylamine (70 mL, 502 mmol). The resulting solution was cooled to 0 C and trifluoroacetic anhydride (34 mL, 241 mmol) was added slowly over 15 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. Then the reaction mixture was poured into a 3 L separatory funnel containing saturated aqueous NaHCO3 solution (500 mL). The aqueous layer was extracted with dichloromethane (2 x 1.2 L) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude reaction mixture was filtered through a short plug of silica gel on a sintered glass funnel, and washed with copious quantities of EtOAc. The resulting filtrate was concentrated under reduced pressure to provide the title compound.Step 2: 2-Bromo-1, 3-thiazole-5-carbonitrile Into a 2 L round-bottom flask containing INTERMEDIATE 1; Ethyl [5-(2-bromo-l, 3-thiazol-5-yl)-2//-tetrazol-2-yl]acetate; Step 1 : 2-Bromo-l, 3-thiazole-5-carboxamide; Into a 2 L round-bottom flask was added ethyl 2-bromothiazole-5-carboxylate (50.0 g, 212 mmol), THF (500 mL) and MeOH (250 mL). To this was added concentrated ammonium hydroxide in water (590 mL) and the reaction mixture was stirred at room temperature for 4 h. The solvents were removed under reduced pressure and the crude mixture poured into a separatory funnel containing brine (1 L). The aqueous layer was extracted with EtOAc (4 x 500 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure.INTERMEDIATE 1; Ethyl [5-(2-bromo-l , 3-thiazol-5-ylV2//-tetrazol-2-yl]acetate; Step 1 2-Bromo-L3-fhiazole-5-carboxarmde; Into a 2 L round-bottom flask was added ethyl 2-bromothiazole-5-carboxylate (50 O g, 212 mmol), THF (500 mL) and MeOH (250 mL) To this was added concentrated 5 ammonium hydroxide m water (590 mL) and the reaction mixture was stirred at room temperature for 4 h The solvents were removed under reduced pressure and the crude mixture poured into a separatory funnel containing brine (1 L) The aqueous layer was extracted with EtOAc (4 x 500 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressureInto a 2 L round-bottom flask was added ethyl 2-bromothiazole-5-carboxylate (50.0 g, 212 mmol), THF (500 mL) and MeOH (250 mL). To this mixture was added concentrated ammonium hydroxide in water (590 mL) and the reaction mixture was stirred at room temperature for 4 h. The solvents were removed under reduced pressure, and the resulting crude mixture poured into a separatory funnel containing brine (1 L). The aqueous layer was extracted with EtOAc (4 x 500 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound.Step 1: 2-Bromo-1, 3-thiazole-5-carboxamide Into a 2 L round-bottom flask was added ethyl 2-bromothiazole-5-carboxylate (50.0 g, 212 mmol), THF (500 mL) and MeOH (250 mL). To this was added concentrated ammonium hydroxide in water (590 mL) and the reaction mixture was stirred at room temperature for 4 h. The solvents were removed under reduced pressure and the crude mixture poured into a separatory funnel containing brine (1 L). The aqueous layer was extracted with EtOAc (4*500 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure.Step 1 2-[3-(2-Chloro-5-iodophenoxy)propoxy)-l , 3-thiazole-5-carboxamideTo a stirred solution of 3-(2-chloro-5-iodophenoxy)propan-l -ol (1 59 g, 5 09 mmol) in DMF (14 mL) cooled to -78 0C was added 60% NaH in oil (495 mg, 12 38 mmol) The reaction mixture was warmed to room temperature for 5-10 mm and cooled again to -78 0C 2- Bromo-l, 3-thiazole-5-carboxamide (1 00 g, 4 84 mmol) was then added and the reaction mixture was allowed to warm to room temperature and heated to 60 0C for 45 mm The suspension was

Molecular Weight:207.05
XLogP3:1.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:205.91495
Monoisotopic Mass:205.91495
Topological Polar Surface Area:84.2
Heavy Atom Count:9
Complexity:132
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes