Benzylamine → [4-(3,3-Dimethyl-ureido)-6,8-dimethoxy-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester

HRID 14646Notes

Reaction equation

HRID 14646 reaction equation
[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13](C(O)=O)=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27]([N:30]([CH:33](C)C)CC)(C)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C([NH2:60])C1C=CC=CC=1.[O:61]1[CH2:66]COCC1>CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([NH:60][C:66]([N:30]([CH3:33])[CH3:27])=[O:61])=[CH:12][N:11]=1)([CH3:3])([CH3:4])[CH3:2]

Participants

7

Reactant 5

HCID 7504BenzylamineHCID 312751,4-DioxaneHCID 81531DiisopropylethylamineHCID 199401P,P-Diphenylphosphinic azideHCID 593410981-(Tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid

Product 1

HCID 68613470[4-(3,3-Dimethyl-ureido)-6,8-dimethoxy-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl esterYield 66%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
95 °C

Procedure

A stirred solution of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid (115 mg, 0.317 mmol) in 8 mL of dioxane, at room temperature, was treated with 49 mg (0.380 mmol, 1.2 eq) diisopropylethyl amine and allowed to stir for 5 minutes. Diphenylphosphoryl azide (96 mg, 1.02 eq) was added dropwise and the reaction was heated to 95° C. After 30 minutes, the reaction was removed from heat, and 46 mg (0.380 1.2 eq) of N-methyl, N-benzylamine was added. The reaction was then heated at 75° C. for 4 h. After cooling to room temperature, the solution was diluted with 15 mL of EtOAc, and was washed sequentially with water, then 1% NH4OH, then brine. The organic phase was dried over MgSO4, filtered through a plug of silica and concentrated. The product was purified by flash chromatography, eluting with 1% MeOH in DCM, to give 101 mg, 66% of the desired urea, as white solid. H1-NMR (CDCl3): δ 8.35 (s, 1H), 7.3-7.4 (m, 5H), 6.77 (s, 1H), 6.45 (s, 1H), 6.34 (s, 1H), 6.30 (s, 1H), 4.94 (d, J=4.7 Hz, 2H), 4.65 (s, 2H), 3.92 (s, 3H), 3.71 (s, 3H), 3.15 (s, 3H), 1.51 (s, 9H). MS: APCI (M+H) calc'd for C26H32N4O5+H=481.6; found 481.0.

Workup

  1. waitAfter 30 minutes
  2. customthe reaction was removed
  3. temperaturefrom heat
  4. temperatureThe reaction was then heated at 75° C. for 4 h
  5. temperatureAfter cooling to room temperature
  6. washwas washed sequentially with water
  7. dry with materialThe organic phase was dried over MgSO4
  8. filtrationfiltered through a plug of silica
  9. concentrationconcentrated
  10. customThe product was purified by flash chromatography
  11. washeluting with 1% MeOH in DCM

Sources & evidence

ORD record
ord-3aa59e78a0694f5b99ff874ac47e1ae9
Source dataset
uspto-grants-2010_06
Patent number
US07732446B1

Reaction notes

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