Triphosgene → HCID 89771165, compound

HRID 711350Notes

Reaction equation

HRID 711350 reaction equation
ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[C:13]1([CH3:29])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C@@H:19]1[NH:24][CH2:23][CH2:22][N:21]2[C:25](=[O:28])[CH2:26][CH2:27][C@@H:20]12.[CH:30]([C:33]1[CH:34]=[C:35]([C@H:43]([NH:45][CH3:46])[CH3:44])[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)([CH3:32])[CH3:31]>CCOC(C)=O.CN(C1C=CN=CC=1)C>[CH:30]([C:33]1[CH:34]=[C:35]([C@H:43]([N:45]([CH3:46])[C:5]([N:24]2[CH2:23][CH2:22][N:21]3[C:25](=[O:28])[CH2:26][CH2:27][C@H:20]3[C@@H:19]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH3:29])=[O:11])[CH3:44])[CH:36]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:38]=1)([CH3:32])[CH3:31]

Participants

6

Reactant 3

HCID 94429TriphosgeneHCID 89771121HCID 89771121, compoundHCID 89771122HCID 89771122, compound

Product 1

HCID 89771165HCID 89771165, compoundYield 49.4%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 8857Ethyl AcetateSolvent3×

Procedure

To a solution of triphosgene (72 mg, 0.242 mmol) in EtOAc (5 mL) at 0° C. was added solution of (1S,8aS)-1-o-tolylhexahydropyrrolo[1,2-a]pyrazin-6(7H)-one (112 mg, 0.484 mmol), DMAP (6.2 mg, 0.05 mmol) and TEA (151 mg, 1.5 mmol) in EtOAc (15 mL). The mixture was stirred for 1.5 h, followed by addition of (R)-1-(3-isopropyl-5-(trifluoromethyl)phenyl)-N-methylethanamine (142 mg, 0.58 mmol) in EtOAc (10 mL) and TEA (151 mg, 1.5 mmol). The reaction was then stirred at 50° C. for 48 h and quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layer was washed with 1 N aqueous HCl solution, dried over anhydrous Na2SO4 and then concentrated in high vacuum. The residue was purified by silica gel chromatography (DCM/MeOH=20/1 to 10/1) to give the title compound (60 mg, yield: 25%) as yellow solid. 1H-NMR (400 MHz, CDCl3) δ ppm 7.37 (s, 1H), 7.27 (d, J=6 Hz, 2H), 7.15 (m, 5H), 5.48 (m, 1H), 4.08 (m, 2H), 3.71 (m, 1H), 2.87 (m, 4H), 2.67 (s, 3H), 2.56 (s, 3H), 2.37 (m, 2H), 1.82 (m, 1H), 1.64 (m, 1H), 1.35 (d, 3H), 1.22 (m, 3H); m/z (ES+): 502 [M+H]+.

Workup

  1. stirringThe reaction was then stirred at 50° C. for 48 h
  2. customquenched with water
  3. extractionThe resulting mixture was extracted with EtOAc
  4. washThe combined organic layer was washed with 1 N aqueous HCl solution
  5. dry with materialdried over anhydrous Na2SO4
  6. concentrationconcentrated in high vacuum
  7. customThe residue was purified by silica gel chromatography (DCM/MeOH=20/1 to 10/1)

Sources & evidence

ORD record
ord-067ed7e02c4444378897c5f731893b60
Source dataset
uspto-grants-2015_11
Patent number
US09181259B2

Reaction notes

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