Formaldehyde → (1R)-9-[(3R,4R)-1,3-dimethylpiperidin-4-yl]-8-(2-fluorophenyl)-1-methyl-3,5-dihydro-1H-[1,2,4]triazino[3,4-c][1,4]benzoxazin-2-one

HRID 519171Notes

Reaction equation

HRID 519171 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 86727575HCID 86727575, compound

Product 1

HCID 86727577(1R)-9-[(3R,4R)-1,3-dimethylpiperidin-4-yl]-8-(2-fluorophenyl)-1-methyl-3,5-dihydro-1H-[1,2,4]triazino[3,4-c][1,4]benzoxazin-2-oneYield 40%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 887MethanolSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of (R)-7-(2-fluoro-phenyl)-4-methyl-6-((3R,4R)-3-methyl-piperidin-4-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride acid (3.05 g, 6.88 mmol) and paraformaldehyde (2.066 g, 68.8 mmol) in MeOH (60 mL) and AcOH (6 mL) was stirred at 80° C. for 16 h. Then, sodium cyanotrihydroborate (0.865 g, 13.76 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 DCM) to give (R)-6-((3R,4R)-1,3-dimethyl-piperidin-4-yl)-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (1.15 g, 40%) as a white solid. The white solid was stirred in HCl/EtOAc (4 M, 50 mL) for 30 min and the reaction mixture was concentrated in vacuo to give (R)-6-((3R,4R)-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 (1.215 g, 39%) as a white solid. 1H NMR (400 MHz, MeOD) δ 7.44 (m, 1H), 7.32-7.16 (m, 3H), 6.90 (m, 1H), 6.84 (s, 1H), 4.68-4.57 (d, J=13.2 Hz, 2H), 3.57 (m, 1H), 3.25 (m, 1H), 3.05 (m, 2H), 2.86 (m, 1H), 2.79 (s, 3H), 2.50 (m, 1H), 1.91 (m, 2H), 1.48 (d, J=6.8 Hz, 3H), 0.91 (m, 3H). LC/MS (Table 1, Method 5) Rt=2.275 min.; MS m/z: 423 [M+H]+. SFC (Table 1, Method 47), Rt=1.145 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 DCM)

Sources & evidence

ORD record
ord-e1fb056522f246f28f59f30d16789b34
Source dataset
uspto-grants-2015_08
Patent number
US09115151B2

Reaction notes

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