Formaldehyde → (1r)-9-[(3s,4s)-1,3-Dimethylpiperidin-4-Yl]-8-(2-Fluorophenyl)-1-Methyl-3,5-Dihydro[1,2,4]triazino[3,4-C][1,4]benzoxazin-2(1h)-One

HRID 519175Notes

Reaction equation

HRID 519175 reaction equation
Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:22]=[C:21]2[C:12]([N:13]3[C:18]([CH2:19][O:20]2)=[N:17][NH:16][C:15](=[O:23])[C@H:14]3[CH3:24])=[CH:11][C:10]=1[C@H:25]1[CH2:30][CH2:29][NH:28][CH2:27][C@H:26]1[CH3:31].C=O.[B-][C:35]#N.[Na+]>CO.CC(O)=O>[CH3:35][N:28]1[CH2:29][CH2:30][C@H:25]([C:10]2[CH:11]=[C:12]3[C:21](=[CH:22][C:9]=2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[F:2])[O:20][CH2:19][C:18]2[N:13]3[C@H:14]([CH3:24])[C:15](=[O:23])[NH:16][N:17]=2)[C@H:26]([CH3:31])[CH2:27]1

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 20587905Sodium cyanoborohydride [MI]HCID 86727582HCID 86727582, compound

Product 1

HCID 86727584(1r)-9-[(3s,4s)-1,3-Dimethylpiperidin-4-Yl]-8-(2-Fluorophenyl)-1-Methyl-3,5-Dihydro[1,2,4]triazino[3,4-C][1,4]benzoxazin-2(1h)-OneYield 70.2%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 887MethanolSolvent

Procedure

A mixture of (R)-7-(2-fluoro-phenyl)-4-methyl-6-((3S,4S)-3-methyl-piperidin-4-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride acid (3.0 g, 6.74 mmol) and paraformaldehyde (0.506 g, 16.86 mmol) in MeOH (100 mL) and AcOH (10 mL) was stirred at ambient temperature for 2 h. Then, sodium cyanotrihydroborate (0.847 g, 13.49 mmol) was added and the reaction mixture was stirred at ambient temperature for 0.5 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on basified silica gel (eluting with 10% MeOH in EA) to give (R)-6-((3S,4S)-1,3-dimethyl-piperidin-4-yl)-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (2.0 g, 65%) as a white solid. The white solid was stirred in HCl/EtOAc (4 M, 15 mL) for 30 min and the reaction mixture was concentrated in vacuo to give (R)-6-((3S,4S)-1,3-dimethyl-piperidin-4-yl)-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride acid (1.65 g, 53%) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 7.49-7.40 (m, 1H), 7.33-7.17 (m, 3H), 6.91 (s, 1H), 6.85 (s, 1H), 4.99-4.93 (m, 1H), 4.70-4.65 (m, 2H), 3.60-3.50 (m, 1H), 3.25-3.00 (m, 3H), 2.90-2.85 (m, 1H), 2.80 (s, 3H), 2.55-2.45 (m, 1H), 2.01-1.84 (m, 2H), 1.49 (d, J=6.4 Hz, 3H), 1.00-0.90 (m, 3H). LC/MS (Table 1, Method 4) Rt=1.654 min.; MS m/z: 423 [M+H]+. SFC (Table 1, Method 48), Rt=3.206 min.

Workup

  1. stirringthe reaction mixture was stirred at ambient temperature for 0.5 h
  2. concentrationThe reaction mixture was concentrated in vacuo
  3. customthe residue was purified by column chromatography on basified silica gel (eluting with 10% MeOH in EA)

Sources & evidence

ORD record
ord-419ea072d1a7418d91f504162d979b0a
Source dataset
uspto-grants-2015_08
Patent number
US09115151B2

Reaction notes

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