3-Bromo-6-chloro-2-methylpyridine

To a 2L 3-neck RBF was added CHTo a solution of 5-bromo-6-methyl-pyridin-2-ylamine (2.0 g, 10.6 mmol) in concentrated HCl (10 mL) was added NaNOTo a stirred solution of 3-bromo-6-c oro-2-me1hylpyridine (105 g, 509 mmol) in CCI4 (2 L) was added N-bromosuccinimide (95 g, 534 mmol) followed by AIBN (8.35 g, 50.9 mmol). The reaction was brought to reflux for 24 hours and then cooled to r.t, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 60% methylene chloride heptanes afforded 144.7 g of semi-pure product. Further purification by SFC on a Chiralpak AD-H column with 20% IPA/CO2 [the conditions of the preparative separation were as follows: column Chiralpak AD-H (2.1x25 cm, 5 um particle size) (Chiral Technologies, West Chester, PA, USA); mobile phase 20% 2-propanol/C02; elution mode isocratic pump-mixed; flow rate 50 mL rnin; pressure 100 bar.] gave 3-bromo-2-(bromomethyl)-6-cMoropyridine.LCMS - 285.7 (M+l)+ *H NMR (CDC13> 500 MHz) delta 7.81 (d, J= 8.4 Hz, 1H), 7.15 (d, J= 8.3 Hz, 1H), 4.63 (s, 2H).To a stirred solution of A solution of To a 2L 3-neck RBF was added CH2Cl2 (900 mL) followed by 2-amino-6-methyl- 5-bromopyridine (74.23 g, 0.39 mol), pyridine-HCl (139 g, 1.2 mol), NaNO2 (83.26 g, 1.2 mol) and CuCl (3.76 g, 5% w/w to starting material). The mixture was cooled to 0-10 0C in an ice- water bath and cone. HCl (4.5 mL, 6% v/w to starting material) was added dropwise and the mixture stirred at 0-10 0C for 30 min. The cooling bath was removed and the mixture was stirred at rt for Ih. The reaction mixture was quenched with saturated aqueous NaHCO3 (400 mL), the layers separated and the aqueous layer was extracted with CH2Cl2 (100 mL). The combined organic layers were concentrated to dryness and hexanes (750 mL) was added to the residue under stirring. The solid was filtered and washed with hexane and the filtrate was concentrated to dryness to afford pure product as a light yellow crystalline solid (61 g, 70%).To a solution of 5-bromo-6-methyl-pyridin-2-ylamine (2.0 g, 10.6 mmol) in concentrated HCl (10 mL) was added NaNO2 (1.1 g, 15.9 mmol) at room temperature. The reaction was stirred for 2 hours, then cooled to 0 C., made basic with NaOH and extracted with Et2O. The Et2O layer was dried (MgSO4) and concentrated in vacuo to give 55A (0.63 g, 28%). HPLC Rt=2.29 min.A solution of 6-amino-3-bromo-2-methylpyridine (239 g, 1278 mmol) in concentrated HC1 (1.0 L) was cooled to -5 C. A solution of sodium nitrite (238 g, 3450 mmol) in water (1.0 L) was added dropwise over 1 hour while maintaining the temperature of the reaction between -5 and 5 C. After the addition was complete, the reaction was stirred for 1 hour, and then the cooling bath was removed and the reaction was warmed to r.t. and stirred for 16 hours. The reaction was then poured onto ice and 5N NaOH (1.7 L) was added to adjust the pH of the solution to 13. The mixture was extracted 3 times with EtOAc (3 L and 2 x 2L). The combined organic layers were dried over NajSC^, filtered, and concentrated. Purification of the residue by flashchromatography on silica gel with 100% methylene chloride afforded 3 -bromo-6-chloro-2- methylpyridine. 1H NMR (CDCI3, 500 MHz) delta 7.76 (d, J= 8.2 Hz, 1H), 7.07 (d, J - 8.1 Hz, 1H), 2.66 (s, 3H).A solution of 6-amino-3-bromo-2-methylpyridine (239 g5 1278 mmol) in concentrated HCl (1.0 L) was cooled to -5 C. A solution of sodium nitrite (238 g, 3450 mmol) in water (1.0 L) was added dropwise over 1 hour while maintaining the temperature of the reaction between -5 and 5 C. After the addition was complete, the reaction was stirred for 1 hour, and then the cooling bath was removed and the reaction was warmed to r.t. and stirred for 16 hours. The reaction was then poured onto ice and 5N NaOH (1.7 L) was added to adjust the pH of the solution to 13. The mixture was extracted 3 times with EtOAc (3 L and 2 x 2L). The combined organic layers were dried over Na2S04, filtered, and concentrated. Purification of the residue by flashchromatography on silica gel with 100% methylene chloride afforded 3-bromo-6-chloro-2- methylpyridine. NMR (CDC13, 500 MHz) 6 7.76 (d, J= 8.2 Hz, 1H), 7.07 (d, J= 8.1 Hz, 1H), 2.66 (s, 3H).Sodium nitrite (4.5 g, 66 mmol) was added slowly to a solution of 6-amino-3-bromo-2-methylpyridine (3.07 g, 16.4 mmol) in concentrated HCl (40 mL) at -20 0C. After 1 h, the reaction was allowed to warm to room temperature and stirred overnight. The reaction was carefully neutralized with ice-cold 5N- NaOH until pH=l 1. The aqueous layer was extracted with Et2O (3 x 75 mL). The combined organic layers were washed with brine (Ix 75 mL), dried (Na2SO4) and concentrated in vacuo to afford 3-bromo- Step 1: Preparation of l-(4-(6-chloro-2-methylpyridin-3-yl)phenyl)pyrrolidin-2-one. [0819] l-(4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (904 mg, 3.15 mmol), To a mixture of NaH (387.20 mg, 9.68 mmol, 60% purity) in DMF (20 mL) was added 2, 2, 2-trifluoroethanol (731.52 _, , 10.16 mmol) under N2 at 0C and the mixture was stirred at 0 C for 0.5 hour. Then 3-Bromo-6-chloro-2-methylpyridine (200 mg, 0.969 mmol), tert-butyl (2-oxopiperidin-4-yl)carbamate (249 mg, 1.162 mmol), Pd2(dba)3(89 mg, 0.0972 mmol), Xantphos (112 mg, 0.194 mmol), cesium carbonate (947 mg, 2.907 mmol) were stirred in dioxane (10 mL) overnight at 100C under nitrogen, cooled and concentrated to give the product after column chromatography ( 31 mg, yield 9.4%).

Molecular Weight:206.47
XLogP3:2.9
Hydrogen Bond Acceptor Count:1
Exact Mass:204.92939
Monoisotopic Mass:204.92939
Topological Polar Surface Area:12.9
Heavy Atom Count:9
Complexity:99.1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes