4-BENZYL-2-MORPHOLINECARBOXYLIC ACID HYDROCHLORIDE

4-benzylmorpholine-2-carbonitrile (64.1 g, 316.9 mmol) was dissolved in 6N HCl aqueous solution (600 mL), refluxed for 2.5 hours, and cooled to -10. The produced solid was filtered, and washed with acetone (300 ml, cooled to -10). The resultant solid compound was dried in a 60 oven so as to provide 4-benzylmorpholine-2-carboxylic acid hydrochloride compound (78.7 g, 305.4 mmol, 96 percent).[107] General procedure: A mixture of the corresponding carboxylic acid (1.0 equiv.), an appropriate amine (2 equiv.), propylphosphonic anhydride (4 equiv.) and N, N- diisopropylethylamine (3.0 equiv.) was stirred in THF or acetonitrile at an elevated temperature for 3 - 16 h. After complete reaction the mixture was purified by silica gel chromatography or by preparative liquid chromatographyExample 43Synthesis of 4-(3-{3-[4-(1-Aminocyclobutyl)phenyl]-2-(2-aminopyridin-3-yl)-3H-imidazo[4, 5-b]pyridin-5-yl}phenyl)-N, N-dimethylmorpholine-2-carboxamide trihydrochloride Step 14-Benzyl-N, N-dimethylmorpholine-2-carboxamideOxalyl chloride (372 muL, 4.27 mmol) was added to a mixture of 4-benzylmorpholine-2-carboxilic acid hydrochloride (1.00 g, 3.88 mmol) and N, N-dimethylformamide (15.0 muL, 0.194 mmol) in DCE (20 mL). The mixture was heated at 65 C. for 3 hours. After cooling to 0 C., Me2NH (2M solution in THF, 9.70 mL, 19.4 mmol) was added. The mixture was stirred at room temperature for 4 hours. The mixture was concentrated and the residue was diluted with water and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to afford desired product (803 mg, 83.4%) as brown oil.400 MHz 1H-NMR (CDCl3) delta: 7.40-7.21 (m, 5H), 4.28 (dd, J=10.3 Hz and 2.5 Hz, 1H), 3.97-3.90 (m, 1H), 3.71 (td, J=11.3 Hz and 2.4 Hz, 1H), 3.58 (d, J=13.3 Hz, 1H), 3.54 (d, J=13.3 Hz, 1H), 3.05 (s, 3H), 2.95-2.86 (m, 1H), 2.92 (s, 3H), 2.72-2.65 (m, 1H), 2.44-2.35 (m, 1H), 2.27 (td, J=11.4 Hz and 3.2 Hz, 1H); LCMS [M+H]: 249. (100 mg, 0.39 mmol) was dissolved in CH2Cl2 (3 ml), and added with BOP (173 mg, 0.39 mmol) and DIPEA (152 mg, 1.17 mmol), followed by stirring. The resultant mixture was added with methyl 4-aminoadamantane-1-carboxylate (82 mg, 0.39 mmol), followed by stirring at room temperature for 12 hours. After the reaction was completed, the organic layer was separated by CH2Cl2 and H2O, and dried and filtered with MgSO4. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:1) so as to provide N-[5-(methoxycarbonyl)tricyclo[3, 3, 1, 13, 7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide (120 mg, 0.29 mmol, 75 %).[743] 1H NMR (400 MHz, CDCl3) delta 7.33-7.25 (m, 5H), 6.93-6.87 (m, NH, 1H), 4.08-4.00 (m, 2H), 3.96-3.93 (m, 1H), 3.75-3.68 (m, 4H), 3.61-3.58 (m, 1H), 3.52-3.49 (m, 1H), 3.27-3.24 (m, 1H), 2.70-2.67 (m, 1H), 2.20-2.13 (m, 1H), 2.05-1.95 (m, 7H), 1.91-1.90 (m, 3H), 1.82-1.79 (m, 3H), 1.62-1.59 (m, 1H). (100 mg, 0.39 mmol) was dissolved in CH2Cl2 (3 ml), and added with EDCI (150 mg, 0.78 mmol) and DMAP (95 mg, 0.78 mmol), followed by stirring. The resultant mixture was added with 2-adamantanol (60 mg, 0.39 mmol), followed by reflux-stirring for 3 hours. After the reaction was completed, the organic layer was separated by CH2Cl2 and H2O, and dried and filtered with MgSO4. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:1) so as to provide adamantyl 4-benzylmorpholine-2-carboxylate (76 mg, 0.21 mmol, 55 %).[656] 1H NMR (400 MHz, CDCl3) delta 7.35-7.26 (m, 5H), 4.30-4.27 (m, 1H), 4.08-4.03 (m, 1H), 3.89 (m, 1H), 3.73-3.68 (m, 1H), 3.62-3.59 (m, 1H), 3.50-3.47 (m, 1H), 2.99-2.96 (m, 1H), 2.57-2.48 (m, 2H), 2.35-2.30 (m, 1H), 2.10-1.50 (m, 14H). (100 mg, 0.39 mmol) was dissolved in CH2Cl2 (2 ml), and added with BOP (173 mg, 0.39 mmol) and DIPEA (152 mg, 1.17 mmol), followed by stirring. The resultant mixture was added with (2S, 4S)-1, 7, 7-trimethylbicyclo[2.2.1]heptane-2-amine (66 mg, 0.429 mmol), followed by stirring at room temperature for 5 hours. After the reaction was completed, the organic layer was separated by CH2Cl2 and H2O, and dried and filtered with MgSO4. The resultant mixture was purified by column chromatography (EA/n-Hex = 1:1) so as to provide 4-benzyl-N-((2S, 4S)-1, 7, 7-trimethylbicyclo [2.2.1]heptane-2-yl)morpholine-2-carboxyamide (57 mg, 0.16 mmol, 50 %).[636] 1H NMR (400 MHz, CDCl3) delta 7.33-7.24 (m, 5H), 6.62-6.60 (m, NH, 1H), 4.27-4.21 (m, 1H), 4.09-4.05 (m, 1H), 3.96-3.93 (m, 1H), 3.75-3.69 (m, 1H), 3.62-3.58 (m, 1H), 3.52-3.48 (m, 1H), 3.29-3.24 (m, 1H), 2.70-2.67 (m, 1H), 2.39-2.31 (m, 1H), 2.21-2.14 (m, 1H), 2.04-1.99 (m, 1H), 1.83-1.73 (m, 1H), 1.70-1.67 (m, 1H), 1.55-1.48 (m, 1H), 1.44-1.36 (m, 1H), 1.32-1.22 (m, 2H), 1.97 (m, 3H), 1.90 (m, 3H), 0.81 (m, 3H).[637] (162.0 mg, 0.63 mmol) was dissolved in CH2Cl2 (5 ml), added with EDCI (121 mg, 0.63 mmol) and DMAP (154 mg, 1.26 mmol), and stirred for 30 minutes. The resultant mixture was added with nortropine (95.4 mg, 0.75 mmol), and stirred at room temperature for 12 hours. The resultant solution was added with H2O, extracted (X3) with CH2Cl2, and dried and filtered with MgSO4. Through vacuum distillation, the solvent was removed. The resultant mixture was purified by column chromatography so as to provide (4-benzylmorpholine-2-yl)(3-hydroxy-8-azabicyclo[3.2.1]ontane-8-yl)methanone (152.0 mg, 0.46 mmol, 73 %).[618] 1H NMR (400 MHz, CDCl3) delta.39-7.23 (m, 5H), 4.65 (m, 1H), 4.48-4.11 (m, 3H), 3.97-3.93 (m, 1H), 3.74-3.67 (m, 1H), 3.60-3.50 (m, 2H), 2.94-2.86 (m, 1H), 2.71-2.68 (m, 1H), 2.42-1.62 (m, 10H).

Molecular Weight:257.71
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:257.0818711
Monoisotopic Mass:257.0818711
Topological Polar Surface Area:49.8
Heavy Atom Count:17
Complexity:238
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes