tert-Butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate synthesis

Yield: 100%

Reaction Conditions:

with potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ in 1,4-dioxane;dimethyl sulfoxide at 90; for 3 h;Inert atmosphere;

Steps:

192.1
Example 192 4-((3 S,4S)- 1 -( 1 -cyanocyclopropanecarbonyl)-4-methylpyrrolidin-3 -ylamino)-6-(6- (dimethylcarbamoyl)pyridin-3-yl)pyrrolo[l,2-b]pyridazine-3-Step 1; tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)picolinate [00357] A reaction vial was charged with tert-butyl 5-bromopicolinate (0.50 g, 1.937 mmol), potassium acetate (0.380 g, 3.87 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(l,3,2-dioxaborolane) (0.590 g, 2.325 mmol) in dioxane (3.69 mL) and DMSO (0.184 mL). The resulting mixture was sparged with argon for ~ 5 min. then PdCl₂(dppf)-CH₂Cl₂ adduct (0.079 g, 0.097 mmol) was added and the resulting mixture was heated at 90 °C for 3h. After cooling to rt, the mixture was partitioned between EtOAc (300 mL) and water (80 mL) and the layers were separated. The organic portion was washed with water (100 mL x 2), brine, then dried over MgS04, filtered and concentrated to afford dark oil as the crude product mixture. This material was purified via ISCO columnchromatography (Hex/EtOAc; 24g silica column) to afford after isoaltion andconcentration of the desired fractions 0.60 g (~ quant.) of a near white solid as the title compound. HPLC (method B) retention time = 2.07 min. ^XH NMR (400MHz,CHLOROFORM-d) δ 9.05 (s, IH), 8.17 (dd, J=7.8, 1.7 Hz, IH), 7.99 (dd, J=7.7, 0.9 Hz, IH), 1.28 (s, 9H), 1.25 (s, 12H).

References:

BRISTOL-MYERS SQUIBB COMPANY;WROBLESKI, Stephen T.;DAS, Jagabandhu;DUAN, Jingwu;GUO, Junqing;HYNES, John;JIANG, Bin;KEMPSON, James;LIN, Shuqun;LU, Zhonghui;PITTS, William J.;SPERGEL, Steven H.;WU, Hong;YANG, Bingwei Vera WO2012/125893, 2012, A1 Location in patent:Page/Page column 225-226