tert-Butyl bromoacetate → tert-Butyl ((6S,8R)-6-(anilinocarbonyl)-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)acetate

HRID 481251Notes

Reaction equation

HRID 481251 reaction equation
[NH:1]([C:8]([C@H:10]1[N:14]2[C:15](=[O:41])[C:16]([N:19]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)C(=O)OCC3C=CC=CC=3)=[CH:17][N:18]=[C:13]2[CH:12]([CH3:42])[CH2:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56]>C1COCC1>[NH:1]([C:8]([C@H:10]1[N:14]2[C:15](=[O:41])[C:16]([NH:19][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:40])[F:38])[CH:32]=3)=[CH:17][N:18]=[C:13]2[C@:12]([CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])([CH3:42])[CH2:11]1)=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 79177tert-Butyl bromoacetateHCID 2733832Lithium HexamethyldisilazideHCID 86587570Benzyl (6S,8RS)-6-(anilinocarbonyl)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl[3-(trifluoromethyl)benzyl]carbamate

Product 1

HCID 86587569tert-Butyl ((6S,8R)-6-(anilinocarbonyl)-8-methyl-4-oxo-3-{[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)acetateYield 45.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of 12c (0.987 g, 1.71 mmol) in 8.6 mL THF at −78° C., was added LiHMDS (1M in THF, 3.59 mL, 3.59 mmol). The red solution was stirred at −78° C. for 10 min, then a solution of t-butyl bromoacetate (0.278 mL, 1.88 mmol) was added. The reaction was allowed to slowly warm to −50° C. over 1 h, then was quenched with the addition of sat. NH4Cl. The mixture was poured into 50 mL H2O and extracted with 100 mL EtOAc. The organic phase was washed with 0.1N HCl and brine, dried (Na2SO4), and concentrated. The product was purified by flash chromatography (50% EtOAc/hexanes) to afford 432 mg (37%) of 92a. 1H NMR (300 MHz, CDCl3) δ8.94 (br s, 1H), 7.51-7.26 (m, 15H), 7.09 (t, J=7.5, 1H), 5.25-5.13 (m, 3H), 5.06 (dd, J=9.4, 6.0, 1H), 4.85 (br s, 2H), 2.89 (dd, J=13.9, 5.8, 1H), 2.80 (ABq, JAB=16.8, δνAB=91.9, 2H), 2.44 (dd, J=13.5, 9.1, 1H), 1.38 (s, 12H); MS (ESI) 713.2 (M+Na+), 689.4 (M−H+).

Workup

  1. temperatureto slowly warm to −50° C. over 1 h
  2. customwas quenched with the addition of sat. NH4Cl
  3. additionThe mixture was poured into 50 mL H2O
  4. extractionextracted with 100 mL EtOAc
  5. washThe organic phase was washed with 0.1N HCl and brine
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated
  8. customThe product was purified by flash chromatography (50% EtOAc/hexanes)

Sources & evidence

ORD record
ord-15e4fcf9839d416483b9c86916a674a8
Source dataset
uspto-grants-2003_11
Patent number
US06653295B2

Reaction notes

Loading…