2-Bromo-4-thiazolecarboxylicacid

Pale yellow crystals

b) 2-bromothiazole-4-carboxylic Acid To a stirring suspension of the compound of Example 3(a) (32.11 g, 0.127 mol) in 16% HBr (aq) (400 mL) at 0 C. a solution of NaNO2 (9.11 g, 0.132 mol) in water (16 mL) was added. After stirring for 35 min, CuBr (20.6 g, 0.144 mol) was added followed by additional 16% Hbr(aq) (150 mL). The mixture was heated at 70 C. for 1 h and immediately filtered. The filtrate was saturated with NaCl and extracted with ethyl acetate (2*500 mL). The organic phases were combined, dried (MgSO4), filtered and concentrated to a brown solid. This was combined with solid collected by filtration and used without further purification or characterization in the next step.A mixture of A mixture of A mixture of DPPA (6.64 g, 24.0 mmol), TEA (5.0 ml_, 36 mmol), 5-amino-2-methyl- pyridine (2.6 g, 24 mmol) and 2-Bromo-l, 3-thiazole-4-carboxylic acid (200.0 mg, 961 pmol), TEA (671 pL, 4.80 mmol), HATU (547.0 mg, 1.44 mmol) and (R)-N-((S)-l, 3-dihydrospiro[indene-2, 4'- piperidin]-l-yl)-2-methylpropane-2-sulfmamide (352.0 mg, 1.15 pmol, synthesized via Step a of Example 120) were placed into DMF(l5 mL). The reaction mixture was evacuated and refilled 3 times using N2, and the reaction mixture was stirred at 25 C for 1 hour. The mixture was then diluted with EtOAc (100 mL) and the mixture was washed with H20 (30 mL x 5), brine (50 mL), dried over anhydrous Na2S04, filtered and concentrated to give a residue. The residue was purified by silica gel chromatography (ethyl acetate in petroleum ether = 0% to 80%) to afford (S)-N-((S)- '-(2-bromothiazole-4-carbonyl)- 1 , 3- dihydrospiro[indene-2, 4'-piperidin]-l-yl)-2-methylpropane-2-sulfmamide (458 mg, 96% yield) as yellow oil. LC-MS (ESI+) m/z: 498.0 (M+H)+.(f?)-/V-((ri)-l, 3-dihydrospiro[indene-2, 4'-piperidin]-l-yl)-2-methylpropane-2- sulfmamide (352.0 mg, 1.15 mmol, synthesized via Step a of Example 120), 2-bromo-l, 3- thiazole-4-carboxylic acid (200 mg, 961 pmol), HATEG (547 mg, 1.44 mmol) and TEA (671 pL, 4.80 mmol) were placed into DMF(lO mL). The reaction mixture was stirred at 25 C for 12 hour. The mixture was diluted with EtOAc (100 mL) and the mixture was washed with H20 (30 mL x 5), brine (50 mL), dried over anhydrous Na2S04, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0% to 80%) to afford (R)-N-((S)-] '-(2-bromothiazole-4-carbonyl)- l , 3- dihydrospiro[indene-2, 4'-piperidin]-l-yl)-2-methylpropane-2-sulfmamide (400 mg, 84% yield) as a yellow oil. LC-MS (ESI+) m/z: 498.0 (M+H)+.To a solution of 2-bromothiazole-4- carboxylic acid (200 mg, 0.96 mmol, 1 equiv) and HATU (401 mg, 1.05 mmol, 1.1 equiv) in DMF (1 mL). The mixture was allow to stirr for 30 mins followed by the addition of DIPEA (396 mg, 3.07 mmol, 3.2 equiv) and a solution of the 1- {l [2, 4bis(trifluoromethyl)phenyl]ethyl}-lH-pyrazol-4-amineHydrochloride (344 mg, 0.96 mmol, 1 equiv) in DMF (1 mL) was added. The reaction mixture was kept under stirring for 24 h at RT. Product formation was confirmed with TLC and LCMS and reaction mixture was diluted EtOAc (50 mL) and washed with water (2x50 mL). Organic layer dried over Na2S04 and concentrated under reduced pressure to obtain crude which was further purified by flash column chromatography (EtO Ac/Hexane) to obtain title compound N-(l-(l-(2, 4- bis(trifluoromethyl)phenyl)ethyl)- lH-pyrazol-4-yl)-2-bromothiazole-4-carboxamide as off white solidO (360 mg). LCMS: 515 [M+H]+.To a solution of The alcohol was dissolved in dimethylformamide (DMF) (300 mL) and imidazole (36.8 g, 0.54 mol) was added. Then a solution of TBS-C1 (81.5 g, 0.54 mol) in tetrahydrofuran (THF) (200 mL) was added dropwise at room temperature. The reaction mixture was stirred overnight, and then water (100 mL) was added. The resulting mixture was extracted with EtOAc (100 mLx3). The combined organic phases were washed with aqueous 5% KHS0 (200 mLx3), saturated aqueous NaHCO, (200 mLx3) and brine (200 mLx 1), dried over anhydrous Na2S04 and concentrated to dryness. The residue was purified by distillation under reduced pressure to afford compound 1 (bpl30~l40C/l3.3 pa, 96.1 g, 74 % yield) as an oil.According to GP1 , commercially available 2-bromo-1 , 3-thiazole-4-carboxylic acid (CAS: 5198-88-9, 816 mg, 3.92 mmol), commercially available 5-fert-butyl-1 , 2-oxazol-3-amine (CAS: 55809-36-4, 500 mg, 3.57 mmol), HATU (1 .49 g, 3.92 mmol) and DIPEA (680 muIota_, 3.90 mmol) were stirred in DMF (7 mL) for 29 h. The obtained crude material was purified by Biotage (column: KP-SIL-100 g, gradient: hexane/EtOAc: 20% to 50% EtOAc), giving the desired amide INT-2 (928 mg, 68% yield) as an orange solid. 1H- NMR (400 MHz, DMSO-de) delta [ppm]: 1.313 (16.00), 2.518 (0.58), 6.634 (2.56), 8.554 (2.32), 1 1 .1 13 (0.51 ); LC-MS (method 2): Rt = 1 .25 min; MS (ESIpos): m/z = 330 [M+H]+.

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