Methanol → (R)-2-(tert-butylamino)-8-(6-(2-hydroxyethyl)-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-methylquinazolin-4(3H)-one

HRID 1056398Notes

Reaction equation

HRID 1056398 reaction equation
C([O:8][CH2:9][CH2:10][C@@H:11]1[C:15]2[NH:16][C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[N:27]=[C:26]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])[N:25]([CH3:34])[C:24]4=[O:35])=[CH:18][C:14]=2[C:13](=[O:36])[NH:12]1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:30]([NH:29][C:26]1[N:25]([CH3:34])[C:24](=[O:35])[C:23]2[C:28](=[C:19]([C:17]3[NH:16][C:15]4[C@@H:11]([CH2:10][CH2:9][OH:8])[NH:12][C:13](=[O:36])[C:14]=4[CH:18]=3)[CH:20]=[CH:21][CH:22]=2)[N:27]=1)([CH3:32])([CH3:33])[CH3:31]

Participants

6

Reactant 4

HCID 887MethanolHCID 25135Boron Trichloride2×HCID 516892Sodium BicarbonateHCID 118511955(R)-8-(6-(2-(benzyloxy)ethyl)-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-(tert-butylamino)-3-methylquinazolin-4(3H)-one

Product 1

HCID 89784110(R)-2-(tert-butylamino)-8-(6-(2-hydroxyethyl)-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-methylquinazolin-4(3H)-oneYield 51.7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of (R)-8-(6-(2-(benzyloxy)ethyl)-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-(tert-butylamino)-3-methylquinazolin-4(3H)-one (503b, 555 mg, 1.14 mmol) in DCM (30 mL) at 0° C. was added boron trichloride (1.0 M in DCM, 1.71 mL, 1.71 mmol) slowly dropwise. The resulting tan suspension was stirred at 0° C. for 5 min, then RT for 15 min. LC-MS indicated only unreacted starting material. The reaction mixture was treated with additional BCl3 solution (0.5 mL) at RT and stirred 10 min. LC-MS indicated product formation. The reaction was cooled to 0° C. in an ice bath and treated with MeOH (ca. 3 mL) and ca. 500 mg of powdered NaHCO3 and stirred for 5 min. The reaction mixture was then treated with silica gel and purified on an ISCO Combiflash RF (40 g Silicycle column, using a gradient of 0-20% MeOH in DCM) affording (R)-2-(tert-butylamino)-8-(6-(2-hydroxyethyl)-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrolo-2-yl)-3-methylquinazolin-4(3H)-one (503) (233 mg, 0.589 mmol, 51.5% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (1H, s), 7.88 (2H, dd, J=7.6, 2.5 Hz), 7.66 (1H, br. s.), 7.18 (1H, t, J=7.7 Hz), 6.72 (1H, d, J=1.4 Hz), 5.93 (1H, s), 4.54 (1H, dd, J=8.8, 3.9 Hz), 3.52-3.83 (6H, m), 1.95-2.09 (1H, m), 1.55-1.67 (1H, m), 1.45-1.54 (9H, s). m/z (ESI, +ve) 396.0 (M+1)+.

Workup

  1. waitRT for 15 min
  2. stirringstirred 10 min
  3. temperatureThe reaction was cooled to 0° C. in an ice bath
  4. stirringstirred for 5 min
  5. additionThe reaction mixture was then treated with silica gel
  6. custompurified on an ISCO Combiflash RF (40 g Silicycle column

Sources & evidence

ORD record
ord-9b6d391e62c84c5691f83b1fc424d3c1
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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