Bromide ion → (4aS,13aR)-8-bromo-10-[(phenylmethyl)oxy]-2,3,4a,5,13,13a-hexahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazine-9,11-dione

HRID 406924Notes

Reaction equation

HRID 406924 reaction equation
[NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][NH2:7].CN(C=O)C.[Br:13][C:14]1[C:15](=[O:36])[C:16]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:17]([C:24](OC)=[O:25])[N:18]([CH2:20][CH:21](O)O)[CH:19]=1.[Br-]>C(#N)C.C(O)(=O)C>[Br:13][C:14]1[C:15](=[O:36])[C:16]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:17]2[C:24](=[O:25])[N:7]3[CH2:6][C@H:2]4[CH2:3][CH2:4][CH2:5][N:1]4[C@@H:21]3[CH2:20][N:18]2[CH:19]=1

Participants

7

Reactant 4

HCID 259Bromide ionHCID 6228DimethylformamideHCID 3034041(2R)-2-PyrrolidinemethanamineHCID 58277223Methyl 5-bromo-1-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate

Product 1

HCID 46239162(4aS,13aR)-8-bromo-10-[(phenylmethyl)oxy]-2,3,4a,5,13,13a-hexahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazine-9,11-dioneYield 78%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
15 °C

Procedure

A reactor was charged with [(2R)-2-pyrrolidinylmethyl]amine (0.75 kg) and 4.6 L of DMF was added followed by 0.45 kg of glacial acetic acid. Acetonitrile (41.4 L) was then added and the mixture was agitated for 15 minutes. To the reaction mixture was added methyl 5-bromo-1-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate (2.30 kg). After stirring for 20 minutes at ambient temperature, the mixture was heated at 75-85° C. until the bromide starting material was consumed by HPLC analysis (about 6 hrs). Upon completion, the mixture was cooled until the refluz subsided and then charged with 6.9 L of methanol and the mixture was heated at reflux for about 45 minutes then cooled to 15° C. and filtered and dried to provide (4aS,13aR)-8-bromo-10-[(phenylmethyl)oxy]-2,3,4a,5,13,13a-hexahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-9,11-dione (1.93 kg, 78%) as a white solid.). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.65 (m, 1H), 7.54 (m, 2H), 7.33 (m, 3H), 5.15 (d, 1H), 4.99 (d, 1H), 4.60 (m, 1H), 4.36 (m, 1H), 4.03 (m, 1H), 3.90 (m, 1H), 3.65 (m, 1H), 3.06-2.84 (m, 3H), 1.92-1.60 (m, 4H).

Workup

  1. additionwas added
  2. stirringAfter stirring for 20 minutes at ambient temperature
  3. customwas consumed by HPLC analysis (about 6 hrs)
  4. temperatureUpon completion, the mixture was cooled until the refluz
  5. additioncharged with 6.9 L of methanol
  6. temperaturethe mixture was heated
  7. temperatureat reflux for about 45 minutes
  8. filtrationfiltered
  9. customdried

Sources & evidence

ORD record
ord-6084a3eec52c4c51a0204cbf5541aa49
Source dataset
uspto-grants-2014_06
Patent number
US08754214B2

Reaction notes

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