Dimethylformamide → 2-(3-Chloro-4-fluorophenyl)-N5-(2-methyl-1-(trifluoromethoxy)propan-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide

HRID 920731Notes

Reaction equation

HRID 920731 reaction equation
[F:1][C:2]([F:12])([F:11])[O:3][CH:4]1[CH2:7][CH:6](C(O)=O)C1.[CH:13]1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[Cl:30][C:31]1[CH:32]=[C:33]([C:38]2[C:46]([C:47]([NH2:49])=[O:48])=[C:41]3[CH2:42][NH:43][CH2:44][CH2:45][N:40]3[N:39]=2)[CH:34]=[CH:35][C:36]=1[F:37].C[N:51]([CH:53]=[O:54])C>C1(C)C=CC=CC=1>[Cl:30][C:31]1[CH:32]=[C:33]([C:38]2[C:46]([C:47]([NH2:49])=[O:48])=[C:41]3[CH2:42][N:43]([C:53]([NH:51][C:7]([CH3:6])([CH3:13])[CH2:4][O:3][C:2]([F:1])([F:11])[F:12])=[O:54])[CH2:44][CH2:45][N:40]3[N:39]=2)[CH:34]=[CH:35][C:36]=1[F:37]

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 199401P,P-Diphenylphosphinic azideHCID 1180616272-(3-Chloro-4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamideHCID 1180617393-(Trifluoromethoxy)cyclobutane-1-carboxylic acid

Product 1

HCID 1180614602-(3-Chloro-4-fluorophenyl)-N5-(2-methyl-1-(trifluoromethoxy)propan-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamideYield 7%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
90 °C

Procedure

To a stirred solution of Intermediate 212C (95 mg, 0.509 mmol) in toluene (5 ml) was added TEA (0.118 mL, 0.848 mmol), DPPA (0.047 mL, 0.204 mmol) and the reaction mixture was stirred at 90° C. for 1 h. The reaction mixture was cooled RT and to it was added a solution of Intermediate 185B (50 mg, 0.170 mmol) in DMF (2 ml) and stirred at RT for 16 h. The reaction was quenched with a 10% aqueous solution of NaHCO3 and extracted with EtOAc (2×20 mL). The combined organic layer dried over Na2SO4, filtered and the filtrate evaporated. The crude compound was purified by preparative HPLC to afford Compound 212 as an off-white solid (6 mg, 7% yield). HPLC retention times 9.95 min. and 9.08 min. (Methods A and B respectively). MS(ES): m/z 478 [M+H]+; 1H NMR (400 MHz, MeOH-d1) δ ppm 7.75-7.77 (m, 1H), 7.58-7.62 (m, 1H), 7.29-7.33 (t, J=8.84 Hz, 1H), 4.85 (s, 2H), 4.23 (s, 2H), 4.18-4.21 (t, J=5.24 Hz, 2H), 3.90-3.92 (t, J=5.24 Hz, 2H), 1.37 (s, 6H).

Workup

  1. temperatureThe reaction mixture was cooled RT and to it
  2. stirringstirred at RT for 16 h
  3. customThe reaction was quenched with a 10% aqueous solution of NaHCO3
  4. extractionextracted with EtOAc (2×20 mL)
  5. dry with materialThe combined organic layer dried over Na2SO4
  6. filtrationfiltered
  7. customthe filtrate evaporated
  8. customThe crude compound was purified by preparative HPLC

Sources & evidence

ORD record
ord-9f57b9e43c4e40b5bdcda860fae86d4e
Source dataset
uspto-grants-2016_03
Patent number
US09273058B2

Reaction notes

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