N-methyl-2-pyrrolidone → 4-[1-(9-hydroxy-2-isopropyl-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrazino[1,2-c]pyrimidin-6-ylmethyl)-cyclopentyl]-benzonitrile

HRID 2169277Notes

Reaction equation

HRID 2169277 reaction equation
C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:29][CH2:30][N:31]([CH:34]([CH3:36])[CH3:35])[C:32](=[O:33])[C:10]=12)C1C=CC=CC=1.[CH3:37][N:38]1CCCC1=O>O.[Zn].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([C:37]#[N:38])=[CH:24][CH:23]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)[N:11]2[CH2:29][CH2:30][N:31]([CH:34]([CH3:36])[CH3:35])[C:32](=[O:33])[C:10]=12

Participants

8

Reactant 2

HCID 13387N-methyl-2-pyrrolidoneHCID 867259269-benzyloxy-6-[1-(4-bromophenyl)-cyclopentylmethyl]-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione

Product 1

HCID 867259274-[1-(9-hydroxy-2-isopropyl-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrazino[1,2-c]pyrimidin-6-ylmethyl)-cyclopentyl]-benzonitrileYield 55.53%

Reagents, catalysts & solvents 5

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 23994ZincCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolvent

Conditions

Temperature
120 °C

Procedure

A stirred solution of 9-benzyloxy-6-[1-(4-bromophenyl)-cyclopentylmethyl]-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (234) (100 mg, 0.182 mmol) in N-Methyl-2-pyrrolidon (1 mL) in a sealed tube was purged with argon for 10 min. To this solution, Zn (1.188 mg, 0.018 mmol), 1,1′-bis(diphenylphosphino)ferrocen (3.021 mg, 0.0050 mmol), Zn(CN)2 (17.067 mg, 0.145 mmol) and Pd2(dba)3 (3.327 mg, 0.0040 mmol) were added and the reaction mixture was heated at 120° C. for 16 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate, washed with water, followed by brine, separated, dried over sodium sulfate and evaporated to get a crude product which was purified by normal silica column using 10% methanol in dichloromethane containing 10% ammonia to get 4-[1-(9-hydroxy-2-isopropyl-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrazino[1,2-c]pyrimidin-6-ylmethyl)-cyclopentyl]-benzonitrile (235) (41 mg, 55.53%) as an off-white solid.

Workup

  1. customAfter completion of the reaction
  2. extractionextracted with ethyl acetate
  3. washwashed with water
  4. customseparated
  5. dry with materialdried over sodium sulfate
  6. customevaporated
  7. customto get a crude product which
  8. customwas purified by normal silica column

Sources & evidence

ORD record
ord-9ff16992b6aa4593a16979b4cdc9d54a
Source dataset
uspto-grants-2015_06
Patent number
US09045486B2

Reaction notes

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