Triphosgene → HCID 118061548, compound

HRID 920811Notes

Reaction equation

HRID 920811 reaction equation
[C:1]([C:3]1([NH:8]S(C(C)(C)C)=O)[CH2:7][CH2:6][O:5][CH2:4]1)#[N:2].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:27][C:28]1[CH:29]=[C:30]([C:35]2[C:43]([C:44]([NH2:46])=[O:45])=[C:38]3[CH2:39][NH:40][CH2:41][CH2:42][N:37]3[N:36]=2)[CH:31]=[CH:32][C:33]=1[F:34]>C1COCC1.O>[Cl:27][C:28]1[CH:29]=[C:30]([C:35]2[C:43]([C:44]([NH2:46])=[O:45])=[C:38]3[CH2:39][N:40]([C:16]([NH:8][C:3]4([C:1]#[N:2])[CH2:7][CH2:6][O:5][CH2:4]4)=[O:18])[CH2:41][CH2:42][N:37]3[N:36]=2)[CH:31]=[CH:32][C:33]=1[F:34]

Participants

6

Reactant 3

HCID 94429TriphosgeneHCID 1180616272-(3-Chloro-4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamideHCID 118062127HCID 118062127, compound

Product 1

HCID 118061548HCID 118061548, compoundYield 26%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of Intermediate 334B (30.3 mg, 0.204 mmol) and TEA (0.142 mL, 1.018 mmol) in THF (8 mL) was added triphosgene (54.4 mg, 0.183 mmol) at 0° C. and the reaction mixture was stirred for 30 min at the same temperature. A solution of Intermediate 185B (60 mg, 0.204 mmol) in THF (1 mL) was added and the reaction mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×15 mL). The combined organic layer was dried over sodium sulfate, filtered and the filtrate concentrated. The crude product was purified by preparative HPLC to afford Compound 334 as an off-white solid (20.6 mg, 23%). HPLC retention time 7.12 and 7.33 min (Methods B and C respectively). MS(ES): m/z=433 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.86 (dd, J=7.28, 2.26 Hz, 1H), 7.65-7.72 (m, 2H), 7.44-7.51 (m, 1H), 7.17-7.41 (m, 2H), 4.79 (s, 2H), 4.16-4.23 (m, 3H), 3.81-3.96 (m, 5H), 2.40-2.49 (m, 2H).

Workup

  1. stirringthe reaction mixture was stirred at RT for 12 h
  2. extractionextracted with ethyl acetate (3×15 mL)
  3. dry with materialThe combined organic layer was dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationthe filtrate concentrated
  6. customThe crude product was purified by preparative HPLC

Sources & evidence

ORD record
ord-a926d90e1d58462892968689ae15ff59
Source dataset
uspto-grants-2016_03
Patent number
US09273058B2

Reaction notes

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