Potassium Phosphate, Tribasic → HCID 129012624, compound

HRID 1056419Notes

Reaction equation

HRID 1056419 reaction equation
Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C@H:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]1)[N:8]([CH3:27])[C:7]2=[O:28].IC1C=CC=C2C=1N=C([NH:40][C@H:41]1[CH2:46][CH2:45][CH2:44][C@@H:43]([NH:47][C:48](=[O:54])OC(C)(C)C)[CH2:42]1)N(C)C2=O.C[C@@H]1C2NC(B3OC(C)(C)C(C)(C)O3)=CC=2C(=O)N1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:27][N:8]1[C:7](=[O:28])[C:6]2[C:11](=[C:2]([C:41]3[NH:40][C:44]4[C@@H:43]([CH3:42])[NH:47][C:48](=[O:54])[C:45]=4[CH:46]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]1[NH:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]1

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 89781988(R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-oneHCID 118520418HCID 118520418, compoundHCID 118520419HCID 118520419, compound

Product 1

HCID 129012624HCID 129012624, compoundYield 17%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of (rac)-tert-butyl ((1R,3S)-3-((8-bromo-3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)carbamate and (rac)-tert-butyl ((1R,3S)-3-((8-iodo-3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)carbamate (509a, 1.49 g, 3.30 mmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705, 1.331 g, 3.96 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloropalladium (II) (0.117 g, 0.165 mmol), and potassium phosphate (2.102 g, 9.90 mmol) in 1,4-dioxane (26.4 mL)/water (6.60 mL) was sparged with nitrogen for 3 min at RT; the red reaction mixture was then heated to 80° C. for 1 h. More (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (0.33 g) was added, and the reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was diluted with EtOAc (150 mL), added to a separatory funnel, and washed with saturated aqueous NaHCO3 (3×100 mL); the aqueous layer was extracted with EtOAc (4×100); the organic layers were separated, dried over Na2SO4, and concentrated. The crude product was loaded onto the column and was purified via automated flash chromatography (silica gel) with 0-8% 2 M ammonia in MeOH/DCM to give (rac)-tert-butyl ((cis)-3-((3-methyl-8-((R)-6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)carbamate (509, 0.59 g, 0.582 mmol, 17% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05-1.34 (m, 3H) 1.37 (s, 9H) 1.40 (d, J=6.65 Hz, 3H) 1.42-1.54 (m, 2H) 1.73-1.89 (m, 2H) 1.99-2.20 (m, 2H) 3.44 (s, 3H) 3.92-4.11 (m, 1H) 4.48-4.59 (m, 0.5; H) 4.60-4.74 (m, 0.5; H) 6.79-6.99 (m, 3H) 7.15 (t, J=7.73 Hz, 1H) 7.63 (d, J=4.30 Hz, 1H) 7.82 (d, J=7.04 Hz, 1H) 7.97 (dd, J=11.54, 7.82 Hz, 1H) 11.99 (br. s., 0.4; H) 12.09 (br. s., 0.6; H). MS (ESI, pos. ion) m/z: 507.2 (M+1).

Workup

  1. customwas sparged with nitrogen for 3 min at RT
  2. additionMore (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (0.33 g) was added
  3. additionThe reaction mixture was diluted with EtOAc (150 mL)
  4. additionadded to a separatory funnel
  5. washwashed with saturated aqueous NaHCO3 (3×100 mL)
  6. extractionthe aqueous layer was extracted with EtOAc (4×100)
  7. customthe organic layers were separated
  8. dry with materialdried over Na2SO4
  9. concentrationconcentrated
  10. customwas purified

Sources & evidence

ORD record
ord-79abf7f36ae6428b9a9af17f60c9c85b
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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