4-Morpholin-4-ylpyridin-2-amine

4-morpholin-4-ylpyridin-2-amine 4-chloropyridin-2-amine (800 mg, 6.22 mmol) was combined with morpholine (8.0 mL) in 2 mL DMA in a sealed vessel. This mixture was heated in the microwave (CSA Discover) for 5 minutes at 200C. Upon cooling, the reaction was concentrated in vacuo and purified via silica gel chromatography (eluent : 95/5/0. 5 CH2CI2/MEOH/NH40H) to give 837 mg of the product as a yellow solid. Yield : 75percent. 1H NMR (DMSO-d6) D 7.70-7. 64 (m, 1H), 6.59-6. 54 (m, 1H), 6.05-6. 00 (m, 1H), 3.74-3. 65 (m, 4H), 3.45-3. 37 (m, 4H). Mass Spectral Data Calculated Mass: 179.20 Found Mass: 180.11 (FOR MH+) Elemental Analysis Calculated for C9H13N3O1#0.1 H2O C, 59.72 ; H, 7.35 ; N, 23.21 Found C, 59.66 ; H, 7.25 ; N, 23.20General procedure: A solution of 2-bromo-1-(5-bromo-2, 4-dimethoxyphenyl)ethanone 7 (124 rng, 0.367 mmol) and 4-(pyrrolidin-1-yl)pyridin-2-amine 8 (60 mg, 0.367 mmol) in acetone (4 mL) was heated at 75 C for 16 h. The reaction mixture was cooled to room temperature; the white precipitate was collected by filtration and solid was washed with acetone. The solid was suspended in aqueous ammonia solution (10 ml.) and stirred for 2 h. The free base was collected by filtration and solid was washed with water, dried under reduced pressure to yield 2-(5-bromo-2, 4-dimethoxyphenyl)-7-(pyrrolidin-1-yl)imidazo[1, 2-a]pyridine 9a (51 mg, 35%) as an off-white solid. 1H NMR (300 MHz, CDCl3): delta 8.55 (s, 1H), 7.83 (d, J = 7.4 Hz, 1H), 7, 80 (s, 1H), 6.55 (s, 1H), 6, 43 (d, J = 2.2 Hz, 1H), 6.33 (dd, J = 2, 2, 7, 4 Hz, 1H), 3 , 99 (s, 3H), 3 , 94 (s, 3H), 3.40-3, 30 (m, 4H), 2.10-2.00 (m, 4H); HPLC (Method 2) >99% (AUC), tR= 19.12 min: APCI MS m/z 404 [M + H]+.To a stirred solution of (4, S)-7-(2-methylpyridin-4-yl)-2, 3, 4, 5-tetrariydro-l, 4- methanopyrido[2, 3-£][l, 4]diazepine (300 mg, 1.189 mmol) in Tetrahydrofuran (30 mL) were added triethylamine (0.829 mL, 5.94 mmol) and triphosgene (353 mg, 1.189 mmol) under nitrogen atmosphere at room temperature and stirred at rt for 1 h. Then 4- morpholinopyridin-2-amine (320 mg, 1.783 mmol) was added to the reaction mixture and stirred at 70 C for 16 h. (TLC System: 10% MeOH in DCM, Rr0A; UV active). The reaction mixture was cooled to rt and partitioned between water (30 mL) and EtOAc (3X30 mL). The combined organic layer was washed with brine solution, dried over anhydrous Na2S04, filtered and filtrate was evaporated to give crude. The crude compound was purified by column chromatography (Silica gel: Neutral alumina, Eluent: 20% EtOAc in Pet ether) to afford the desired product (4, S)-7-(2-methylpyridin-4-yl)-N-(4- mo holinopyridin-2-yl)-3, 4-dihydro-l, 4-methanopyrido[2, 3-^][l, 4]diazepine-5(2H)- carboxamide (145 mg, 0.312 mmol, 26.3 % yield) as an off white solid. LCMS (m/z): 458.29 [M+H]+, Rt = 1.23 min.1H NMR (400 MHz, CDC13): delta 13.40 (s, 1 H), 8.61 (d, J = 5.2 Hz, 1 H), 8.24 (d, J = 1.8 Hz, 1 H), 8.09 (d, J= 6.0 Hz, 1 H), 7.79 (d, J= 2.4 Hz, 1 H), 7.75 - 7.68 (m, 1 H), 7.61 (d, J = 8.0 Hz, 1 H), 7.48 (d, J = 7.9 Hz, 1 H), 6.45 (dd, J = 6.0, 2.5 Hz, 1 H), 5.68 (dd, J = 6.0, 3.2 Hz, 1 H), 3.88 - 3.80 (m, 4 H), 3.40 - 3.32 (m, 4 H), 3.32 - 3.20 (m, 2 H), 3.24 - 3.13 (m, 1 H), 3.01 (dd, J= 12.1, 3.3 Hz, 1 H), 2.73 (s, 3 H), 2.40 - 2.26 (m, 1 H), 2.08 (dt, J= 14.9, 7.7 Hz, 1 H).To a stirred solution of 4-bromopyridin-2-amine (0.5 g, 2.89 mmol), dicyclohex- yl(2', 4', 6'-triisopropylbiphenyl-2-yl)phosphine (0.110 g, 0.23 mmol), pd2dba3 (0.106 g, 0.12 mmol) and morpholine (1.26 mL, 14.5 mmol) in tetrahydrofuran (5.8 mL). To this mixture was added LHMDS in THF (1.0M, 15.89 mL, 15.9 mmol) and the resulting reaction was heated to 65 C and stirring continued for 1.75 h. After which, the reaction was cooled to room temperature and then poured into water (100 mL) and extracted with ethyl acetate (2 x 150 mL) and dichloromethane (2 x 150 mL). The combined organic layers were dried over magnesium sulfate and the crude product was purified on alumina ( 0 to 100% ethyl acetate hexane) to give A solution of 4-chloro-pyridin-2-ylamine (800 mg, 6.22 mmol) and morpholine (8.1 mL, 93.34 mmol) in N-methyl-2-pyrrolidone (NMP) (2 mL) was heated in a microwave (Emry's Optimizer) at 200 C. for 10 minutes. The resulting solution was directly purified by flash chromatography (SiO2, 95:5:0.5/DCM:MeOH:NH4OH) to give 3-(6-Methoxypyridin-3-yl)-4-(2-{4-[(4-morpholin-4-ylpyridin-2-yl)amino]butyl}-1, 3- THIAZOL-4-YL) butanoic acid hydrochloride [00195] STEP G Dissolve ethyl 3- (6-METHOXYPYRIDIN-3-YL)-4- [2- (4-OXOBUTYL)-1, 3-THIAZOL-4- YL] butanoate (374mg, 1.0 MMOL) and [00188] STEP G (3S)-ETHYL 3- (1, 3-BENZODIOXOL-5-YL)-4-2-F4-R (4-MORPHOLIN-4-YLPYRIDIN-2- VI) AMINOLBUTYLL-1, 3-THIAZOL-4-YL) BUTANOATE HYDROCHLORIDE DISSOLVE (3S)-ETHYL 3- (1, 3-BENZODIOXOL-5-YL)-4- [2- (4-OXOBUTYL)-1, 3-THIAZOL- 4-YL] butanoate (230 mg, 0.6 MMOL) and

Molecular Weight:179.22
XLogP3:0.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:179.105862047
Monoisotopic Mass:179.105862047
Topological Polar Surface Area:51.4
Heavy Atom Count:13
Complexity:159
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes