Formaldehyde → (S)-3-(3,4-difluorophenyl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6,6,8-trimethyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepine-1-carboxamide

HRID 75123Notes

Reaction equation

HRID 75123 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH2:14][C:15]([CH3:20])([CH3:19])[CH2:16][NH:17][CH2:18][C:12]3=[C:11]([C:21]([NH:23][C@@H:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:25]([NH:27][CH3:28])=[O:26])=[O:22])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C=O.[C:35]([O-])(=O)C.[K+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH2:14][C:15]([CH3:20])([CH3:19])[CH2:16][N:17]([CH3:35])[CH2:18][C:12]3=[C:11]([C:21]([NH:23][C@@H:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:25]([NH:27][CH3:28])=[O:26])=[O:22])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]

Participants

8

Reactant 5

HCID 712FormaldehydeHCID 516892Sodium BicarbonateHCID 517044Potassium AcetateHCID 5049666Sodium triacetoxyborohydrideHCID 66660428(S)-3-(3,4-difluorophenyl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6,6-dimethyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepine-1-carboxamide

Product 1

HCID 66660458(S)-3-(3,4-difluorophenyl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6,6,8-trimethyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepine-1-carboxamideYield 9%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

The product from step 2 above (181 mg, 0.23 mmol) was dissolved in 2 mL of THF and treated sequentially with 37% aqueous formaldehyde (63 μL, 2.30 mmol) and potassium acetate (45 mg, 0.46 mmol) and the mixture stirred for 10 minutes. Sodium triacetoxyborohydride (146 mg, 0.69 mmol) was added and stirring continued for 1.5 hours. The reaction was quenced by the addition of 5 mL of saturated aqueous NaHCO3 and 10 mL of DCM was added. The layers were separated and the aqueous layer was extracted with 10 mL of DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO RediSep-4, gradient elution 0%-20% EtOH:acetonitrile). The residue was lyophilized from aqueous acetonitrile to give 85 mg (9% yield) of (S)-3-(3,4-difluorophenyl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6,6,8-trimethyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepine-1-carboxamide as a white powder. LCMS (+ESI) m/z: 462.3 [MH]+1. 1H-NMR (DMSO d6) δ 8.07 (m, 1H), 7.64-7.48 (m, 3H), 7.35-7.28 (m, 1H), 5.06-4.32 (bs, 2H), 4.24 (d, 1H), 3.91-3.66 (m, 2H), 2.52 (d, 3H), 2.40-2.32 (m, 2H), 2.27 (s, 3H), 1.08 (s, 9H), 0.85 (s, 9H), 0.66 (s, 3H), 0.59 (s, 3H).

Workup

  1. stirringstirring
  2. waitcontinued for 1.5 hours
  3. additionwas added
  4. customThe layers were separated
  5. extractionthe aqueous layer was extracted with 10 mL of DCM
  6. dry with materialThe combined organic phases were dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified by column chromatography (ISCO RediSep-4, gradient elution 0%-20% EtOH:acetonitrile)

Sources & evidence

ORD record
ord-3e0ce4f89a064e19b6e95b8946159126
Source dataset
uspto-grants-2014_09
Patent number
US08835422B2

Reaction notes

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