Formaldehyde → Tert-butyl 3-methyl-3-(methyl(1-methyl-2-oxo-8-(trifluoromethyl)-3-((2-(tri methylsilyl)ethoxy)methyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)amino)azetidine-1-carboxylate

HRID 519060Notes

Reaction equation

HRID 519060 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([CH3:41])([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:30])([F:29])[F:28])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:40])[C:18](=[O:39])[N:19]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.CO.[BH3-][C:47]#N.[Na+]>CC(O)C.CC(O)=O>[CH3:41][C:10]1([N:12]([CH3:47])[C:13]2[C:26]([C:27]([F:29])([F:28])[F:30])=[CH:25][C:24]3[O:23][CH2:22][C:21]4=[N:20][N:19]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:37])[CH3:38])[C:18](=[O:39])[CH:17]([CH3:40])[N:16]4[C:15]=3[CH:14]=2)[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11]1

Participants

7

Reactant 4

HCID 712FormaldehydeHCID 887MethanolHCID 5003444Sodium cyanoborohydrideHCID 867273933-Methyl-3-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 86727426Tert-butyl 3-methyl-3-(methyl(1-methyl-2-oxo-8-(trifluoromethyl)-3-((2-(tri methylsilyl)ethoxy)methyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)amino)azetidine-1-carboxylateYield 53%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolvent2×HCID 3776IsopropanolSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of 3-methyl-3-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (Example #100, Step A, 0.250 g, 0.417 mmol) and paraformaldehyde (neat, 0.250 g, 8.34 mmol) in iPrOH (5 mL) and AcOH (0.5 ml) was stirred at 110° C. for 2 days. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. Then, MeOH (5 mL), AcOH (2.5 mL) and NaBH3CN (0.524 g, 8.34 mmol) were added. The mixture was stirred at 60° C. for 1 h. The reaction mixture was cooled to ambient temperature and solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether) to give tert-butyl 3-methyl-3-(methyl(1-methyl-2-oxo-8-(trifluoromethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)amino)azetidine-1-carboxylate (0.135 g, 53%). 1H NMR (CDCl3, 400 MHz): δ 7.25 (s, 1H), 6.72 (s, 1H), 5.10 (m, 2H), 4.65 (m, 1H), 4.66 (q, J=13.2 Hz, 2H), 4.03 (d, J=8.8 Hz, 1H), 3.90 (d, J=12.4 Hz, 1H), 3.66 (t, 2H), 3.58 (t, 2H), 2.68 (s, 3H), 1.48 (s, 3H), 1.47 (d, J=6.4 Hz, 3H), 1.42 (s, 9H), 0.99 (m, 2H), 0.00 (s, 9H).

Workup

  1. temperatureThe reaction mixture was cooled to ambient temperature
  2. customthe solvent was removed in vacuo
  3. stirringThe mixture was stirred at 60° C. for 1 h
  4. temperatureThe reaction mixture was cooled to ambient temperature
  5. customsolvent was removed in vacuo
  6. customThe residue was purified by column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether)

Sources & evidence

ORD record
ord-bc209c7cac2042f9ba8e334817b9066a
Source dataset
uspto-grants-2015_08
Patent number
US09115151B2

Reaction notes

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