3-BROMO-2-CHLORO-5-FLUOROPYRIDINE

Light yellow powder

To a solution of urea compound with hydrogen peroxide (1 : 1) (1.34, 14.3 mole) and trifluoroacetic anhydride (2 mL, 14.3 mole) in 10 mL dichloromethane at 0 C for at least 15 minutes was added 3- fluoro-5-bromopicolinonitrile (500 mg, 2.38 mmol). The reaction mixture was stirred at 40 C for 2 hours. The reaction quenched with saturated aqueous NaHC03 (20 mL) and then extracted with DCM (20 mL x 5). The combined organics were dried over anhydrous Na2SC'4 and concentrated to give the crude title compound, which was carried forward without purification. MS: 226, 228 (M+l).A mixture of 4-bromo-l-(((3R, 4R)-3, 4-difluorocyclopentyl)methyl)-lH-pyrazole (INTERMEDIATE D6, 80 mg, 0.302 mmol), bis(pinacolato)diboron (92 mg, 0.362 mmol), (0372) PdCl2(dppf) (22.1 mg, 0.030 mmol) and KOAc (59.2 mg, 0.604 mmol) in 1, 4-dioxane (3 ml) was stirred at 80 C for 16 hours under N2. LCMS confirmed boronate formation. 3-Bromo-2-chloro-5- fluoropyridine (95 mg, 0.452 mmol), K3PO4 (241 mg, 0.903 mmol) and PdCl2(dppf) (22.0 mg, 0.030 mmol) were then added, the vessel evacuated and charged with nitrogen, then water (1 ml) was added and the reaction stirred at 80 C for 16 hours under N2. The mixture was dissolved in EtOAc (20 ml), washed with water (5 ml), dried over Na2S04, filtrated and the filtrate was concentrated, purified by silica gel chromatography (pet. ether: THF = 80: 20) to give the title compound. MS (M+l): 316.To a solution of n-BuLi/THF (1.45 mL, 2.5 mol/L) in THF (5 mL) was added asolution of Step 1: 3-bromo-2-cyclopropyl-5-fluoropyridine [00222] To a solution of Step 1 : 3-bromo-2-cyclopropyl-5-fluoropyridine [00248] To a solution of Example 222alpyrimidine-3-carboxamido)propylcarbamate; Step A: Preparation of (RVtert-butyl 2-(2-chloro-5-fluoropyridin-3- yDpyrrolidine- 1 -carboxylate:; A solution of tert-butyl pyrrolidine- 1-carboxylate (1 mL 5.70 mmol) and (-)-sparteine (1.31 mL, 5.70 mmol) in anhydrous MTBE (30 mL) was first cooled to -78 0C under nitrogen, followed by addition of sec-butyl lithium (4.07 mL, 1.4M, 5.70 mmol) drop-wise over 15 minutes with a syringe, maintaining the temperature below -75 0C. The pale yellowish solution was stirred at -78 0C for 3 hours before being treated with zinc chloride (3.80 mL, 1.0 M, 3.80 mmol) dropwise over 15 minutes while maintaining the temperature below -73 0C. The mixture was stirred at -78 0C for 30 minutes, then placed into an ambient temperature water bath and stirred for another hour. At this point a large amount of white precipitate was present. The mixture was treated with 3-bromo-2-chloro-5- fluoropyridine (1.00 g, 4.75 mmol) in MTBE (5 mL), followed by addition of palladium acetate (53 mg, 0.24 mmol) and tri-t-butylphosphine tetrafluoroborate (83 mg, 0.28 mmol). The mixture was allowed to stir at ambient temperature overnight to reach completion. The mixture was treated with NH4OH (1 mL), stirred for 30 minutes and filtered through GF/F paper, washing with MTBE. The filtrate was washed with 10% citric acid (30 mL) and the aqueous layer was back-washed with MTBE (2 x 30 mL). The combined organic phases were washed with brine (20 mL), dried (MgSO4), and concentrated to afford the crude product as dark yellowish oil. This crude material was purified on a silica 5O g Biotage SNAP cartridge eluting with 10% EtOAc in hexanes to afford the desired product as colorless oil (0.5 g, 35%). MS (apci pos) m/z = 201.1 (M+H-Boc).To a reaction mixture of 2-(( 1 R, 2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6- ol (140 mg, 0.53 mmol; see Example 3 above) in 1.8 mL of NMP was added cesium carbonate (380 mg, 1.166 mmol) and stirred for 3-5 minutes at room temperature . To this mixture was added

Molecular Weight:210.43
XLogP3:2.6
Hydrogen Bond Acceptor Count:2
Exact Mass:208.90432
Monoisotopic Mass:208.90432
Topological Polar Surface Area:12.9
Heavy Atom Count:9
Complexity:103
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes