5-Bromothiazole-4-carboxylic acid

(a) 5-bromo-1 , 3-thiazole-4-carboxylic acid To a stirred solution of methyl 5-bromo-1, 3-thiazole-4-carboxylate (5.00 g, 22.52 mmol) in THF (80 mL) was added an aq. solution of LiOH.H20 (2.70 g, 112.58 mmol) in H20 (20 mL). The reaction mixture was stirred at room temperature for 18 h. DCM (50 mL) and H20 (20 mL) were then added and the reaction mixture acidified to pH—2 with 2M aqueous HCI, followed by extraction with DCM (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give 5-bromo-1, 3-thiazole-4-carboxylic acid (3.09 g, 66 percent yield) as a yellow solid, which was used without further purification.LC-MS (Method D) 208.3/210.3 [M+H] RT 1.36 mmTo a stirred solution of methyl 5-bromo-1 , 3-thiazole-4-carboxylate (5.00 g, 22.52 mmol) in THF (80 mL) was added an aq. solution of LiOH.HTo a stirred solution of compound LXXX-1 (3 g, 12.69 mmol) in methanol (30 mL), THF (30 mL) and water (30 mL), NaOH (1.52 g, 38.1 mmol) was added. The mixture was stirred at room temperature for 1 hour. The solution was concentrated, then HTo a solution of Example 64a (3.34 g, 14.15 mmol), Example lb (3.27 g, 21.22 mmol) and Na2C03 solution (26 mL, 2.0 M) in DME:EtOH=l : 1, 160 mL) was added Pd(PPh3)4 (3.27 g, 2.83 mmol) at room temperature under N2. The reaction mixture was heated to 110C and stirred overnight under N2. TLC showed the starting material was consumed completely and desired the product was detected. The reaction mixture was filtered and the filter cake was washed with EtO Ac and the filtrates were concentrated. The residue was purified by flash column chromatography (PE: EtOAc=3: 1) to afford the Example 64b (3.7 g, yield 95%) as yellow solid. LCMS [M+H]+=326.1(a) 5-bromo-1 , 3-thiazole-4-carboxylic acid To a stirred solution of methyl 5-bromo-1, 3-thiazole-4-carboxylate (5.00 g, 22.52 mmol) in THF (80 mL) was added an aq. solution of LiOH.H20 (2.70 g, 112.58 mmol) in H20 (20 mL). The reaction mixture was stirred at room temperature for 18 h. DCM (50 mL) and H20 (20 mL) were then added and the reaction mixture acidified to pH-2 with 2M aqueous HCI, followed by extraction with DCM (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give To a stirred solution of methyl 5-bromo-1 , 3-thiazole-4-carboxylate (5.00 g, 22.52 mmol) in THF (80 mL) was added an aq. solution of LiOH.H20 (2.70 g, 1 12.58 mmol) in H20 (20 mL). The reaction mixture was stirred at room temperature for 18 h. DCM (50 mL) and H2O (20 mL) were then added and the reaction mixture acidified to pH~2 with 2 M aqueous HCI, followed by extraction with DCM (3 chi 20 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSCU, filtered and concentrated under reduced pressure to give 5-bromo-1 , 3-thiazole-4-carboxylic acid (3.09 g, 66 % yield) as a yellow solid, which was used without further purification. LC-MS (Method D) 208.3/210.3 [M+H]+; RT 1.36 min(b) 5-bromo-N-cyclopropyl- 1, 3-thiazole-4-carboxam ide To a solution of To a solution of 5-bromo-1 , 3-thiazole-4-carboxylic acid (3.09 g, 14.85 mmol) in DCM (75 mL) was added DIPEA (5.17 mL, 29.71 mmol) followed by cyclopropylamine (1.18 mL, 17.08 mmol) and HATU (6.21 g, 16.34 mmol). The reaction mixture was allowed to stir at room temperature for 6 h. The mixture was then diluted with H2O (50 mL) and the layers were separated. The aqueous layer was further extracted with DCM (3 chi 25 mL) and the combined organics dried over MgSCU, filtered and concentrated under reduced pressure. The crude reaction product was purified by flash chromatography eluting with a gradient system of 0-50% EtOAc in Petroleum ether (40-60) to give 5-bromo-N-cyclopropyl-1 , 3- thiazole-4-carboxamide (2.88 g, 78 % yield) as a white solid.LC-MS (Method D) 247.2/249.2 [M+H]+; RT 1.82 min150 mg (0.43 mmol) of Intermediate 12 5-Bromothiazole-4-carboxylic acid (2.17g, 10.4mmol) was dissolved in dry dioxan (170ml_) and heated at 100C. To this, Lambda/, /V-dimethyl-formamide di-tert-butyl acetal (13.68g, 67.28mmol) was added drop wise and the mixture stirred at 100C for 1 hour. The mixture was cooled to room temperature and stirred for 18 hours. The volatile solvents were removed in vacuo and the residue partitioned between water and diethyl ether. The organic layer was washed with saturated NaHC03, dried with Na2S04, filtered and concentrated in vacuo to dryness. The residue was purified by chromatography on silica eluting with 0-20% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in vacuo to give Intermediate 12 (2.8g) as a yellow solid. 1 H NMR (CDCIs) delta: 8.76 (1 H, s), 1 .63 (9H, s) LCMS (Method 2) Rt 3.23 min; m/z(M+H)+ 265Step 12-(5-Bromo-thiazol-4-yl)-5-methyl- 1 H-benzoimidazole A solution of To a stirred solution of compound LXXX-1 (3 g, 12.69 mmol) in methanol (30 mL), THF (30 mL) and water (30 mL), NaOH (1.52 g, 38.1 mmol) was added. The mixture was stirred at room temperature for 1 hour. The solution was concentrated, then H20 (20 mL) was added, and the mixture was extracted with EtOAc (50 mL x 3). The organic layer was combined and washed with brine, dried over Na2S04, concentrated in vacuo to afford compound LXXX-2 (2.2 g, yield 83%).To a stirred solution of compound LXXX 2 (0.7 g, 3.37 mmol), compound LXXX-2A (0.53 g, 4.36 mmol), TEA (677 mg, 6.7 mmol) in toluene (10 mL) was added DPPA (1.2 g, 4.36 mmol) under nitrogen. After the addition, the solution was heated to reflux under nitrogen over night. The solution was concentrated. The residue was purified by column chromatography on silica gel (Petroleum ether:EtOAc = 3: 1) to afford compound LXXX-3 (0.76 g, yield 69%). MS (ESI) m/z (M+Na)+ 350.9.

Molecular Weight:208.04
XLogP3:1.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:206.89896
Monoisotopic Mass:206.89896
Topological Polar Surface Area:78.4
Heavy Atom Count:9
Complexity:132
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes