1,1'-Carbonyldiimidazole → 1,3-Dioxo-2-[(1S,2R)-2-phenylcyclopropyl]-N-(4-phenylisoxazol-5-yl)hexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxamide

HRID 1260475Notes

Reaction equation

HRID 1260475 reaction equation
[C:1]1([C:7]2[CH:8]=[N:9][O:10][C:11]=2[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1.[C:35]1([C@@H:41]2[CH2:43][C@H:42]2[N:44]2[C:52](=[O:53])[CH:47]3[CH2:48][NH:49][CH2:50][CH2:51][N:46]3[C:45]2=[O:54])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[O:53]=[C:52]1[CH:47]2[CH2:48][N:49]([C:28]([NH:12][C:11]3[O:10][N:9]=[CH:8][C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:29])[CH2:50][CH2:51][N:46]2[C:45](=[O:54])[N:44]1[C@H:42]1[CH2:43][C@@H:41]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1

Participants

6

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 2733832Lithium HexamethyldisilazideHCID 27487854-Phenyl-1,2-oxazol-5-amineHCID 673000522-[trans-2-phenylcyclopropyl]tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-dione

Product 1

HCID 461819261,3-Dioxo-2-[(1S,2R)-2-phenylcyclopropyl]-N-(4-phenylisoxazol-5-yl)hexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxamideYield 30%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

4-Phenylisoxazol-5-amine (2 eq) was dissolved in THF (0.1M) and treated with LiHMDS (0.1N, 2 eq), after stirring for 1 h CDI (1 eq) was added. The suspension was stirred for a further 2 h and then A5 (1 eq, 0.1 M) was added and the reaction stirred 5 h. The reaction was quenched with sat. aq. NH4Cl solution and then extracted with EtOAc. Organic layers were washed with brine, dried and concentrated under reduced pressure. The crude material was purified by preparative RP-HPLC using H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents. The desired fractions were lyophilized to afford the title compound in 30% yield. 1H NMR (400 MHz, DMSO, 300K) δ 9.68 (1H, s), 9.00 (1H, s), 7.54 (2H, m), 7.43 (2H, m), 7.30 (3H, m), 7.23 (3H, m), 4.35 (1H, m), 4.16-4.06 (2H, m), 3.17-2.88 (3H, m), 2.69 (1H, m), 2.42-2.31 (1H, m), 1.61-1.49 (1H, m), 1.45-1.39 (1H, m). MS (ES+) C25H23N5O4 requires 457, found: 458 (M+H)+.

Workup

  1. additionwas added
  2. stirringthe reaction stirred 5 h
  3. customThe reaction was quenched with sat. aq. NH4Cl solution
  4. extractionextracted with EtOAc
  5. washOrganic layers were washed with brine
  6. customdried
  7. concentrationconcentrated under reduced pressure
  8. customThe crude material was purified by preparative RP-HPLC

Sources & evidence

ORD record
ord-59d665ed2e5a468dbd48720e90973210
Source dataset
uspto-grants-2013_06
Patent number
US08470823B2

Reaction notes

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