Acetic Acid → (R)-7-bromo-6-(1,3-dimethyl-azetidin-3-ylamino)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one

HRID 519150Notes

Reaction equation

HRID 519150 reaction equation
[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]3[C:11]([CH2:12][O:13]2)=[N:10][NH:9][C:8](=[O:16])[C@H:7]3[CH3:17])=[CH:4][C:3]=1[NH:18][C:19]1([CH3:23])[CH2:22][NH:21][CH2:20]1.[CH3:24]C(O)=O.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]3[C:11]([CH2:12][O:13]2)=[N:10][NH:9][C:8](=[O:16])[C@H:7]3[CH3:17])=[CH:4][C:3]=1[NH:18][C:19]1([CH3:23])[CH2:20][N:21]([CH3:24])[CH2:22]1

Participants

5

Reactant 3

HCID 176Acetic AcidHCID 5003444Sodium cyanoborohydrideHCID 86727542(R)-7-bromo-4-methyl-6-(3-methyl-azetidin-3-ylamino)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one

Product 1

HCID 86727543(R)-7-bromo-6-(1,3-dimethyl-azetidin-3-ylamino)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-oneYield 62%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

A mixture of (R)-7-bromo-4-methyl-6-(3-methyl-azetidin-3-ylamino)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (4.0 g, 10.4 mmol) and polyformaldehyde (0.78 g, 26 mmol) in MeOH (10 mL) was stirred at ambient temperature for 10 min followed by the addition of AcOH (0.5 mL). The mixture was stirred at ambient temperature for 30 min before the addition of sodium cyanoborohydride (1.4 g, 22.8 mmol). The mixture was stirred at 40° C. overnight. The mixture was cooled to ambient temperature and concentrated in vacuo to give the residue, which was purified by chromatography on silica gel (eluting with 1% methanol in dichloromethane) to give (R)-7-bromo-6-(1,3-dimethyl-azetidin-3-ylamino)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (2.8 g, 62%). 1H NMR (400 MHz, CDCl3) δ=8.77 (s, 1H), 7.14 (s, 1H), 6.01 (s, 1H), 4.63 (q, J=6.8 Hz, 1H), 4.56 (d, J=12.8, 2H), 4.46 (s, 1H), 3.87 (m, 2H), 3.46 (m, 2H), 2.57 (s, 3H), 1.65 (s, 3H), 1.55 (d, J=6.8 Hz, 3H). LC/MS (Table 1, Method 25) Rt=0.659 min.; MS m/z: 394 [M+H]+ and 396 [M+H+2]+.

Workup

  1. stirringThe mixture was stirred at 40° C. overnight
  2. temperatureThe mixture was cooled to ambient temperature
  3. concentrationconcentrated in vacuo
  4. customto give the residue, which
  5. customwas purified by chromatography on silica gel (eluting with 1% methanol in dichloromethane)

Sources & evidence

ORD record
ord-f964c92f5cd04ed1b88863444919194b
Source dataset
uspto-grants-2015_08
Patent number
US09115151B2

Reaction notes

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