(6-BROMO-2-PYRIDINYL)-CARBAMIC ACID,1,1-DIMETHYLETHYL ESTER

Step 1. Preparation of te/f-butyl 6-bromopyridin-2-ylcarbamateTo a solution of 6-bromopyridin-2-amine (3 g, 17.34 mmol), triethylamine (3.14 mL, 22.54 mmol) and DMAP (0.424 g, 3.47 mmol) in DCM (24 mL) was added slowly a solution of BOC-anhydride (4.83 mL, 20.81 mmol) in DCM (6 mL). The reaction mixture was stirred at ambient temperature for -24 hr. The mixture was diluted with water, brine and EtOAc. The separated aqueous layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography providing te/f-butyl 6-bromopyridin-2- ylcarbamate as a white solid. Yield: 1.67 g. LCMS (m/z): 274.9 [M+H]+; Retention time = 0.95 min.To a solution of6-bromopyridin-2-amine (1.0 g, 5.78 mmol), di-tert-butyl dicarbonate25 (1.4 g, 6.2 mmol)in DCM (10 mL)were added triethylamine (1.58 mL, 11.91 mmol)and 4~dimellrylaminopyridine (140 mg, 1.17 mmol). The reaction mixture was stirred at room temperature for 10 h and concentrated in vacuo. The crude residue was purified by silica gelcolumn chromatography (petroleum ether/Et0Ac=10: 1)to give the title compound (1.1 g, 67percent)as a white solid. 1HNMR (400 MHz, CDCl3)8 7.55-7.48 (m, 1H), 7.31 (d, J= 8.0 Hz, 1H), 7.19 (t, J = 4.0 Hz, 2H), 1.44 (s, 9H).62 g (284 mmol) of di-tert-butyl dicarbonate diluted in 200 ml of dichloromethane are added dropwise to A solution of 49.2 g (284 mmol) of 2-amino-6- bromopyridine, 43.4 ml (312 mmol) of triethylamine and 3.5 g (28.4 mmol) of 4-DIMETHYLAMINOPYRIDINE in 400 ml of dichloromethane. The reaction medium is stirred at room temperature for 18 hours. After addition of water and extraction with dichloromethane, the organic phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by thin- layer chromatography on silica eluted with a 95/5 heptane/ethyl acetate mixture. 39 g (50percent) of tert-butyl (6-bromopyrid-2-yl) carbamate are obtained in the form of a white solid.Example 6: 3-{4-[6-(3-Heptyl-l-πtethylureido)pyrid-2- yl]phenyl}propanoic acid; a. text-Butyl (6-bromopyrid-2-yl)carbamate; 62 g (284 mmol) of di-tert-butyl dicarbonate diluted in 200 ml of dichloromethane are added dropwise to a solution of 49.2 g (284 mmol) of 2-amino-6- bromopyridine, 43.4 ml (312 mmol) of triethylamine and 3.5 g (28.4 mmol) of 4-dimethylaminopyridine in 400 ml of dichloromethane. The reaction medium is stirred at EPO Step G; Commercially available 2-amino-6-bromo-pyridine (4.25 g, 24.6 mmol) was dissolved in dichloromethane (50 mL) and N, N'-diisopropylethylamine (5.25 mL, 30.7 mmol) and 4-dimethylaminopyridine (0.1 g. 1.23 mmol) was added. After the addition of a solution of di-tert-butyl dicarbonate (5.9 g, 27 mmol) in dichloromethane (15 mL), the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (100 mL) and washed with 10 percent citric acid (50 mL) and brine (50 mL). The organic phase was separated, dried over NaExample 66: Tert-butyl (6-bromopyridin-2-yl)carbamate; Diphenylphosphoryl azide (10.7 mL, 50 mmol, 1.0 equiv) was added to a solution of 6- bromopyridine-2-carboxylic acid (10.0 g, 50 mmol, 1.0 equiv) and triethylamine (6.8 mL, 50 mmol, 1.0 equiv) in anhydrous ferf-butyl alcohol (250 mL). The reaction mixture was refluxed for 2 hours, concentrated in vacuo and diluted with ethyl acetate. The organic layers were washed with 0.5 M sodium citrate buffer (pH = 4.5), saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified over silica (Biotage Horizon silica gel 40M column) and eluted with 8percent ethyl acetate in hexanes which provided a light yellow solid (8.9 g, 66percent yield): Step GCommercially available 2-amino-6-bromo-pyridine (4.25 g, 24.6 mmol) was dissolved in dichloromethane (50 mL) and N, N'-diisopropylethylamine (5.25 mL, 30.7 mmol) and 4-dimethylaminopyridine (0.15 g, 1.23 mmol) was added. After the addition of a solution of di-tert-butyl dicarbonate (5.9 g, 27 mmol) in dichloromethane (15 mL), the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (100 mL) and washed with 10percent citric acid (50 mL) and brine (50 mL). The organic phase was separated, dried over NaCommercially available 2-amino-6-bromo-pyridine (4.25 g. 24.6 mmol) was dissolved in dichloromethane (50 mL) and N.N'-diisopropylethylamine (5.25 mL, 30.7 mmol) and 4- dimethylaminopyridine (0.15 g, 1.23 mmol) was added. After the addition of a solution of di- tert-butyl dicarbonate (5.9 g, 27 mmol) in dichloromethane ( 1 5 mL), the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane ( 100 mL) and washed with 10 percent citric acid (50 mL) and brine (50 mL). The organic phase was separated, dried over NaStep 1. Preparation of te/f-butyl 6-bromopyridin-2-ylcarbamateTo a solution of 6-bromopyridin-2-amine (3 g, 17.34 mmol), triethylamine (3.14 mL, 22.54 mmol) and DMAP (0.424 g, 3.47 mmol) in DCM (24 mL) was added slowly a solution of BOC-anhydride (4.83 mL, 20.81 mmol) in DCM (6 mL). The reaction mixture was stirred at ambient temperature for -24 hr. The mixture was diluted with water, brine and EtOAc. The separated aqueous layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography providing te/f-butyl 6-bromopyridin-2- ylcarbamate as a white solid. Yield: 1.67 g. LCMS (m/z): 274.9 [M+H]+; Retention time = 0.95 min.To a solution of6-bromopyridin-2-amine (1.0 g, 5.78 mmol), di-tert-butyl dicarbonate25 (1.4 g, 6.2 mmol)in DCM (10 mL)were added triethylamine (1.58 mL, 11.91 mmol)and 4~dimellrylaminopyridine (140 mg, 1.17 mmol). The reaction mixture was stirred at room temperature for 10 h and concentrated in vacuo. The crude residue was purified by silica gelcolumn chromatography (petroleum ether/Et0Ac=10: 1)to give the title compound (1.1 g, 67%)as a white solid. 1HNMR (400 MHz, CDCl3)8 7.55-7.48 (m, 1H), 7.31 (d, J= 8.0 Hz, 1H), 7.19 (t, J = 4.0 Hz, 2H), 1.44 (s, 9H).62 g (284 mmol) of di-tert-butyl dicarbonate diluted in 200 ml of dichloromethane are added dropwise to A solution of 49.2 g (284 mmol) of 2-amino-6- bromopyridine, 43.4 ml (312 mmol) of triethylamine and 3.5 g (28.4 mmol) of 4-DIMETHYLAMINOPYRIDINE in 400 ml of dichloromethane. The reaction medium is stirred at room temperature for 18 hours. After addition of water and extraction with dichloromethane, the organic phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by thin- layer chromatography on silica eluted with a 95/5 heptane/ethyl acetate mixture. 39 g (50%) of tert-butyl (6-bromopyrid-2-yl) carbamate are obtained in the form of a white solid.Example 6: 3-{4-[6-(3-Heptyl-l-?tethylureido)pyrid-2- yl]phenyl}propanoic acid; a. text-Butyl (6-bromopyrid-2-yl)carbamate; 62 g (284 mmol) of di-tert-butyl dicarbonate diluted in 200 ml of dichloromethane are added dropwise to a solution of 49.2 g (284 mmol) of 2-amino-6- bromopyridine, 43.4 ml (312 mmol) of triethylamine and 3.5 g (28.4 mmol) of 4-dimethylaminopyridine in 400 ml of dichloromethane. The reaction medium is stirred at EPO Step G; Commercially available 2-amino-6-bromo-pyridine (4.25 g, 24.6 mmol) was dissolved in dichloromethane (50 mL) and N, N'-diisopropylethylamine (5.25 mL, 30.7 mmol) and 4-dimethylaminopyridine (0.1 g. 1.23 mmol) was added. After the addition of a solution of di-tert-butyl dicarbonate (5.9 g, 27 mmol) in dichloromethane (15 mL), the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (100 mL) and washed with 10 % citric acid (50 mL) and brine (50 mL). The organic phase was separated, dried over Na2SO4, filtered and the solvents were removed. The residue was purified by chromatography on silica using ethylacetate/n-heptane (5/95) to afford the title compound as a white solid (2.15 g, 32 %). Washing the column with ethylacetate/ n-heptane (10/90) afforded the corresponding bis-Boc-derivative as a white solid (1.95 g. 21 %). 1H-NMR (400 MHz, CDCl3): d = 1.52 (s, 9H), 7.13 (d, 1H), 7.27 (br-s, 1H), 7.51 (t, 1H), 7.90 (d, 1H) Bis-Boc derivative: 1H-NMR (400 MHz, CDCl3): d = 1.48 (s, 18H), 7.27 (d, 1H), 7.40 (d. 1H), 7.60 (t, 1H)Step 1. Preparation of To a solution of 6-bromopyridin-2-amine (3 g, 17.34 mmol), triethylamine (3.14 mL, 22.54 mmol) and DMAP (0.424 g, 3.47 mmol) in DCM (24 mL) was added slowly a solution of BOC-anhydride (4.83 mL, 20.81 mmol) in DCM (6 mL). The reaction mixture was stirred at ambient temperature for -24 hr. The mixture was diluted with water, brine and EtOAc. The separated aqueous layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography providing te/f-butyl 6-bromopyridin-2- ylcarbamate as a white solid. Yield: 1.67 g. LCMS (m/z): 274.9 [M+H]+; Retention time = 0.95 min.To a solution of 6-bromopyridin-2-amine (3 g, 17.34 mmol), triethylamine (3.14 mL, 22.54 mmol) and DMAP (0.424 g, 3.47 mmol) in dichloromethane (24 mL) was slowly added a solution of BOC-anhydride (4.83 mL, 20.81 mmol) in dichloromethane (6 mL). The reaction mixture was stirred at room temperature for -24 hrs. The mixture was diluted with water, brine and EtOAc. The separated aqueous layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel] providing To a solution of 6-bromopyridin-2-amine (3 g, 17.34 mmol), triethylamine (3.14 mL, 22.54 mmol) and DMAP (0.424 g, 3.47 mmol) in dichloromethane (24 mL) was slowly added a solution of BOC-anhydride (4.83 mL, 20.81 mmol) in dichloromethane (6 mL). The reaction mixture was stirred at room temperature for ~24 hrs. The mixture was diluted with water, brine and EtOAc. The separated aqueous layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel] providing tert- butyl 6-bromopyridin-2-ylcarbamate (1 .67 g) as a white solid. LCMS (m/z): 274.9 [M+H]+; Rt = 0.95 min.4-(4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxoborolan-2-yl)benzyl)thiomorpholine1, 1-dioxide (2 eq) of Formula (III) was added to a solution of tert-butyl (6-bromopyridin-2-yl) carbamate of Formula (XIII) in 1, 4-dioxane/water (5:1). Potassium carbonate K2CO3 (2 eq.) and PdCl2dppf (5%) were added to above solution. The resulting mixture was then heated in at 100 C. Water was added and the solution was extracted with ethyl acetate to obtain compound of Formula (XV).

Molecular Weight:273.13
XLogP3:2.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:272.01604
Monoisotopic Mass:272.01604
Topological Polar Surface Area:51.2
Heavy Atom Count:15
Complexity:228
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes