6-BROMOPYRIDINE-2-CARBOXYLIC ACID ETHYL ESTER

General procedure: n-BuLi (1.67 M solution in hexane, 1.32 mL, 2.2 mmol) was added dropwise into a solution of p-bromochlorobenzene (383 mg, 2.0 mmol) in THF (3 mL) at -78 °C for 30 min. Then, ethyl formate (1.6 mL, 20 mmol) was added to the mixture and the obtained mixture was stirred at -78 °C. After 3 h at the same temperature, IGeneral procedure: Step 1 : NaH (0.355 g, 15 mmol) was added to a suspension of 6-bromopicolinic acid (12) (1.0 g, 4.9 mmol) and cyclohexylmethanol (0.79 g, 6.90 mmol) in THF (20 mL) at room temperature. The reaction mixture was stirred at 60 C for 18 hours then concentrated under reduced pressure. Methanol (20 ml) was added to the residue followed by 1.25 M HCl/MeOH (10 ml) and cone. H2S04 (1 ml). The resulting mixture was stirred at 60 C for 18 hours, concentrated under reduced pressure, partitioned between saturated NaHC03 (50 ml) and ethyl acetate (100 ml). Organic layer was separated, dried over anhydrous Na2S04 and concentrated under reduced pressure. Crude methyl 6-(cyclohexylmethoxy)picolinate (13) was used in next reaction without purification. Yield (1.22 g, quant.); 1H NMR (400 MHz, DMSO-d6) delta 7.84 (t, J= 8.0 Hz, 1H), 7.63 (d, J= 8.0 Hz, 1H), 7.03 (d, J= 8.4 Hz, 1H), 4.08 (d, J=6.0 Hz, 2H), 3.84 (s, 3H), 1.84-1.58 (m, 6H), 0.88-1.26 (m, 5H).Method D To a solution of Ex 3 hydrochloride (52 mg, 0.126 mmol) in toluene (2 mL), are added ethyl-6-bromopicolinate (43.6 mg, 0.189 mmol, 1.5 eq), NaOtBu (36 mg, 0.379 mmol, 3 eq.), Pd2(dba)3 (11.6 mg, 0.013mmol, 0.1 eq.) and BINAP (16.2 mg, 0.025 mmol, 0.2 eq.). The resulting mixture is degassed and is heated at 110C overnight. The reaction is quenched with 2N HCI aq. (10 mL) and the mixture is diluted with EtOAc. The phases are separated. The organic phase is dried over MgS04, filtered and evaporated. The crude product is purified by prep TLC (eluent: DCM/MeOH: 9/1) to give Ex 18-3 as a yellow solid (10 mg, 17% yield). LCMS-1 : tR = 1.22 min, [M+1]+ 497.34; 1H NMR (400 MHz, CDCh) <5: 8.57 (d, J = 8.0 Hz, 1 H), 7.76-7.66 (m, 1 H), 7.58 (d, J = 7.0 Hz, 1 H), 7.47 (s, 2 H), 7.46-7.33 (m, 3 H), 7.27 (t, J = 70.5 Hz, 1 H), 6.94 (d, J = 8.1 Hz, 1 H), 6.67 (d, J = 7.9 Hz, 1 H), 5-03-4.78 (m, 2 H), 4.69-4.40 (m, 2 H), 2.59-2.47 (m, 1 H), 2.39 (s, 3 H), 1.20 (d, J = 6.4 Hz, 6 H).

Molecular Weight:230.06
XLogP3:2.4
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:228.97384
Monoisotopic Mass:228.97384
Topological Polar Surface Area:39.2
Heavy Atom Count:12
Complexity:163
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes