Triphosgene → HCID 71715426, compound

HRID 711349Notes

Reaction equation

HRID 711349 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.[CH2:30]([C:32]1[CH:33]=[C:34]([C@H:42]([NH:44][CH3:45])[CH3:43])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH3:31]>CCOC(C)=O.CN(C1C=CN=CC=1)C>[CH2:30]([C:32]1[CH:33]=[C:34]([C@H:42]([N:44]([CH3:45])[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])[CH3:43])[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1)[CH3:31]

Participants

6

Reactant 3

HCID 94429TriphosgeneHCID 89771121HCID 89771121, compoundHCID 89771168HCID 89771168, compound

Product 1

HCID 71715426HCID 71715426, compoundYield 32%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 8857Ethyl AcetateSolvent3×

Procedure

To a solution of triphosgene (47 mg, 0.16 mmol) in EtOAc (2 mL) at 0° C. was added solution of (1S,8aS)-1-o-tolylhexahydropyrrolo[1,2-a]pyrazin-6(7H)-one (74 mg, 0.32 mmol), DMAP (4 mg, 0.032 mmol) and TEA (49 mg, 0.48 mmol) in EtOAc (2 mL). The mixture was stirred for 1.5 h, followed by addition of (R)-1-(3-ethyl-5-(trifluoromethyl)phenyl)-N-methylethanamine (111 mg, 0.48 mmol) in EtOAc (2 mL) and TEA (97 mg, 0.963 mmol). The reaction was stirred at 50° C. for 48 h and quenched with water. The resulting mixture was extracted with EtOAc and the organic layer was washed with 1 M aqueous HCl solution, dried over anhydrous Na2SO4 and then concentrated in high vacuum. The residue was purified by Prep-HPLC to give the title compound (25 mg, yield: 17%). 1H NMR (400 MHz, CDCl3) δ ppm 7.34 (s, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.20 (s, 1H), 7.17 (d, J=4.8 Hz, 1H), 7.13 (dd, J=14.9, 7.3 Hz, 2H), 7.06 (s, 1H), 5.49 (q, J=6.8 Hz, 1H), 4.11 (dd, J=20.6, 11.3 Hz, 2H), 3.71 (dd, J=16.8, 7.4 Hz, 1H), 3.28 (d, J=11.9 Hz, 1H), 3.11 (t, J=12.3 Hz, 1H), 2.95 (td, J=11.8, 2.9 Hz, 1H), 2.66 (d, J=10.2 Hz, 4H), 2.61 (d, J=7.6 Hz, 1H), 2.55 (s, 3H), 2.47 (m, 1H), 2.38-2.26 (m, 1H), 1.84 (ddd, J=16.7, 13.0, 3.9 Hz, 1H), 1.67 (ddd, J=17.3, 13.1, 9.3 Hz, 1H), 1.36 (d, J=6.6 Hz, 3H), 1.21 (t, J=7.6 Hz, 3H); m/z (ES+): 488 [M+H]+.

Workup

  1. stirringThe reaction was stirred at 50° C. for 48 h
  2. customquenched with water
  3. extractionThe resulting mixture was extracted with EtOAc
  4. washthe organic layer was washed with 1 M aqueous HCl solution
  5. dry with materialdried over anhydrous Na2SO4
  6. concentrationconcentrated in high vacuum
  7. customThe residue was purified by Prep-HPLC

Sources & evidence

ORD record
ord-4073464eb5544607988ac2fa2ae192dd
Source dataset
uspto-grants-2015_11
Patent number
US09181259B2

Reaction notes

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