Potassium Carbonate → 9-benzyloxy-6-(4-chloro-2-pyridin-3-yl-benzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione

HRID 2169421Notes

Reaction equation

HRID 2169421 reaction equation
[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2Br)[N:11]2[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:29])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)[N:11]2[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:29])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 27343783-Pyridinylboronic acidHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 867260459-benzyloxy-6-(2-bromo-4-chlorobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione

Product 1

HCID 867260539-benzyloxy-6-(4-chloro-2-pyridin-3-yl-benzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dioneYield 50.1%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

In a sealed tube was placed a stirred solution of 9-benzyloxy-6-(2-bromo-4-chlorobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (380) (100 mg, 0.194 mmol) in dioxane (3 mL). Pyridine 3-boronic acid (23.822 mg, 0.194 mmol), and a 1N solution of potassium carbonate [(80.349 mg, 0.581 mmol) dissolved in 1.25 mL water] were added at room temperature, and the reaction mixture was purged with argon for 30 min. Then, Pd(triphenyl phosphine)4 (22.395 mg, 0.019 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (15.911 mg, 0.039 mmol) were added and the reaction mixture was further degassed for another 10 min. The reaction mixture was heated at 80° C. for 4 h (monitored by LC-MS). The reaction mixture was filtered through a pad of cellite and the filtrate was diluted with water (5 mL) and extracted with ethyl acetate (2×20 mL). The combined extracts were dried and concentrated. The resulting crude product was purified by column (using amine bound silica gel) to get 9-benzyloxy-6-(4-chloro-2-pyridin-3-yl-benzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (389) (50 mg, 50.1%) as an off-white solid.

Workup

  1. customIn a sealed tube was placed
  2. customthe reaction mixture was purged with argon for 30 min
  3. customthe reaction mixture was further degassed for another 10 min
  4. filtrationThe reaction mixture was filtered through a pad of cellite
  5. additionthe filtrate was diluted with water (5 mL)
  6. extractionextracted with ethyl acetate (2×20 mL)
  7. customThe combined extracts were dried
  8. concentrationconcentrated
  9. customThe resulting crude product was purified by column (using amine bound silica gel)

Sources & evidence

ORD record
ord-4c52206442894e6eb7f1d14b78b13652
Source dataset
uspto-grants-2015_06
Patent number
US09045486B2

Reaction notes

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