OXETAN-3-AMINE HYDROCHLORIDE

To a solution of 2-bromo-4-fluoropyridine (1.0 g, 5.68 mmol) in NMP (8 mL) was added 50% Propylphosphonic anhydride (T3P) solution in DMF (1.1 mL, 1.748 mmol) was added to a mixture of crude CIS-3-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1, 3-diazaspiro[4.5]decan-3-yl]-propionic acid (INT-899) (300 mg, 0.699 mmol, crude, contaminated with 4-methylbenzene-sulfonic acid), Example 239 Rac-(4bS, 5R, 6R, 7S, 7aR)-7a-(4-bromophenyl)-4b, 5-dihydroxy-4-methoxy-N-(oxetan-3-yl)-7-phenyl-4b, 6, 7, 7a-tetrahydro-5H-cyclopenta[4, 5]furo[2, 3-c]pyridine-6-carboxamide (Cpd. No. 239F) (1488) Synthesis of rac-(4bS, 5R, 6R, 7S, 7aR)-7a-(4-bromophenyl)-4b, 5-dihydroxy-4-methoxy-N-(oxetan-3-yl)-7-phenyl-4b, 6, 7, 7a-tetrahydro-5H-cyclopenta[4, 5]furo[2, 3-c]pyridine-6-carboxamide (Cpd. No. 239F) (1489) To a solution of 801 rac-(4bS, 5R, 6R, 7S, 7aR)-7a-(4-bromophenyl)-4b, 5-dihydroxy-4-methoxy-7-phenyl-4b, 6, 7, 7a-tetrahydro-5H-cyclopenta[4, 5]furo[2, 3-c]pyridine-6-carboxylic acid (1, 1.5 g, 3.0 mmol) in 79 N, N-dimethylformamide (20 mL), 1394 1-[Bis(dimethylamino)methylene]-1H-1, 2, 3-triazolo[4, 5-b]pyridinium 3-oxide hexafluorophosphate (3.43 g, 9.0 mmol) and 49 N, N-diisopropyl ethylamine (2.7 ml, 15.0 mmol) were added at 0 C. and stirred the mixture for 5 min. 2003 A mixture of compound TX63762 (39.7 mg, 0.0764 mmol), TEA (0, 03 mL, 0, 2 mmol), DMAP (20.3 mg, 0.166 mmol), 3 -oxeiananiine hydrochloride {00086504} 82 (17.0 mg, 0.155 mmol) and CH2C12 (2 mL) was stirred at room temperature for 30 min. EDCl (30.6 mg, 0.160 mmol) was added, and the reaction was stirred at room temperature for 8 h. The resultant mixture was diluted with EtOAc, washed with 1 N HCl and brine, dried with Na2S0 , and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in hexanes) to give compound TauChi64Theta44 (28.5 mg, 65%) as a white solid: NMR (400 MHz, CDCL) delta 8.04 (s, 1H), 5.97 (s, 1 H), 5.94 (s, 1H), 6.74 (m, 1H), 4.92 (dt, 2H, J = 2.3, 7.1 Hz), 4.48 (dt, 2H, J = 2.9, 6.4 Hz), 3.06 (d, 1 H, J = 4.6 Hz), 2.20 (m, 3H), 1.69 (m, 1 1H), 1.51 (s, M l ). 1 .50 (s, 3H), 1.26 (s, 3H), 1.25 (m, 4H), 1 .18 (s, 3H), 1.02 (m, 2H), 1.00 (s, 3H), 0.93 (s, 3H), 0.88 (s, 3H); m/z 575.3 (M+l ).Example 117: N-f ^-dimethylphenyn^-fl-hydroxy- -foxetan-S-ylamino^ethyn-N- isobutylbenzenesulfonamide To a stirred solution of N-(2, 4-dimethylphenyl)-N-isobutyl-4-(oxiran-2-yl)benzenesulfonamide (50 mg, 0.139 mmol) in ethanol (1 ml.) at 25 C was added To a stirred solution of N-(2, 4-dimethylphenyl)-N-isobutyl-4-(oxiran-2-yl)benzenesulfonamide (50 mg, 0.139 mmol) in ethanol (1 mL) at 25 C. was added Reference Example 28 N-(oxetan-3-yl)-2-[4-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]ethanamine Oxetan-3-amine hydrochloride (0.092 mg, 1.6 mmol) was added to a solution of [3-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]acetaldehyde (0.30 g, 1.5 mmol) obtained in Reference Example 17 in CHCl3 (10 mL), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.95 g, 4.5 mmol) was added thereto, and the mixture was stirred at room temperature for 24 hours. A saturated aqueous solution of NaHCO3 was added to the reaction solution, followed by extraction with CHCl3. The extracted organic layer was washed with brine and dried over Na2SO4. Then, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (KP-NH 28 g, hexane/EtOAc=80/20'20/80) to obtain the title compound (0.20 g) (colorless oil). MS (ESI pos.) m/z: 263 [M+H]+00871] Alternatively, and as depicted in Scheme 70 above, compound 64 can be synthesized from compound 7 via oxidative cleavage of the diol moiety of 7 using lead tetraacetate to yield dialdehyde 29. Reductive amination of dialdehyde 29 affords oxetane- bearing morpholine analog 64 in a 70 % yield over two steps.

Molecular Weight:109.55
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:2
Exact Mass:109.0294416
Monoisotopic Mass:109.0294416
Topological Polar Surface Area:35.2
Heavy Atom Count:6
Complexity:33.9
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes