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 594840노트

반응식

HRID 594840 반응식
[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

참가 물질

7

반응물 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

생성물 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-dione수율 78%

시약·촉매·용매 2

HCID 176Acetic Acid용매HCID 6342Acetonitrile용매

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온도
15 °C

실험 절차

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 reflux 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).

후처리

  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 reflux
  5. additioncharged with 6.9 L of methanol
  6. temperaturethe mixture was heated
  7. temperatureat reflux for about 45 minutes
  8. filtrationfiltered
  9. customdried

출처 및 근거

ORD 기록
ord-caeca04094ac4c1da6a810717eb51254
출처 데이터셋
uspto-grants-2016_01
특허 번호
US09242986B2

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