Tetrahydrofuran → 2-(3-Chloro-4-fluorophenyl)-N5-(1-((difluoromethoxy)methyl) cyclobutyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide

HRID 920739Notes

Reaction equation

HRID 920739 reaction equation
[F:1][CH:2]([F:12])[O:3][CH2:4][C:5]1(C(O)=O)[CH2:8][CH2:7][CH2:6]1.C1C=CC(P([N:27]=[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].C1[CH2:54][O:53]CC1>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:54]([NH:27][C:5]4([CH2:4][O:3][CH:2]([F:1])[F:12])[CH2:6][CH2:7][CH2:8]4)=[O:53])[CH2:44][CH2:45][N:40]3[N:39]=2)[CH:34]=[CH:35][C:36]=1[F:37]

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 199401P,P-Diphenylphosphinic azideHCID 1180616272-(3-Chloro-4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamideHCID 1180628681-((Difluoromethoxy)methyl)cyclobutanecarboxylic acid

Product 1

HCID 1180617862-(3-Chloro-4-fluorophenyl)-N5-(1-((difluoromethoxy)methyl) cyclobutyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamideYield 15%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
90 °C

Procedure

To a stirred solution of Intermediate 223B (0.024 g, 0.136 mmol) in toluene (1 mL) was added TEA (0.076 mL, 0.543 mmol), DPPA (0.074 mL, 0.339 mmol) and the reaction mixture was heated to 90° C. for 2 h. The reaction mixture was cooled to RT and to it was added a solution of Intermediate 185B (0.040 g, 0.136 mmol) in THF (0.5 mL) and stirred for 12 h. The reaction mixture was quenched with a 10% aqueous solution of NaHCO3 and extracted with EtOAc (3×10 mL) The combined organic layer was washed with water, dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by preparative HPLC to afford Compound 223 as an off-white solid (10 mg, 15%). HPLC retention times 2.35 min. and 2.35 min (Method E and L respectively). MS(ES): m/z=472 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85 (dd, J=7.28, 2.26 Hz, 1H), 7.66-7.71 (m, 1H), 7.42-7.48 (m, 1H), 7.30-7.37 (m, 7.11-7.22 (m, 1H), 6.99 (s, 1H), 6.47-6.87 (m, 1H), 4.72 (s, 2H), 4.09-4.14 (t, J=5.52 Hz, 2H), 4.04 (s, 2H), 3.84 (t, J=5.52 Hz, 2H), 2.04-2.15 (m, 4H), 1.80 (d, J=9.04 Hz, 2H).

Workup

  1. temperatureThe reaction mixture was cooled to RT and to it
  2. customThe reaction mixture was quenched with a 10% aqueous solution of NaHCO3
  3. extractionextracted with EtOAc (3×10 mL) The combined organic layer
  4. washwas washed with water
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationthe filtrate concentrated
  8. customThe crude product was purified by preparative HPLC

Sources & evidence

ORD record
ord-ca4bed33627a462a98f38f252340e8d4
Source dataset
uspto-grants-2016_03
Patent number
US09273058B2

Reaction notes

Loading…