Tetrahydrofuran → HCID 118062283, compound

HRID 920753Notes

Reaction equation

HRID 920753 reaction equation
[F:1][CH:2]([F:10])[C:3]1(C(O)=O)[CH2:6][CH2:5][CH2:4]1.C1C=CC(P([N:25]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[C:44]([C:45]([NH2:47])=[O:46])=[C:39]3[CH2:40][NH:41][CH2:42][CH2:43][N:38]3[N:37]=2)[CH:32]=[CH:33][C:34]=1[F:35].C1[CH2:52][O:51]CC1>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[C:44]([C:45]([NH2:47])=[O:46])=[C:39]3[CH2:40][N:41]([C:52]([NH:25][C:3]4([CH:2]([F:1])[F:10])[CH2:4][CH2:5][CH2:6]4)=[O:51])[CH2:42][CH2:43][N:38]3[N:37]=2)[CH:32]=[CH:33][C:34]=1[F:35]

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 199401P,P-Diphenylphosphinic azideHCID 846493531-(difluoromethyl)cyclobutane-1-carboxylic acidHCID 1180616272-(3-Chloro-4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

Product 1

HCID 118062283HCID 118062283, compoundYield 17%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
90 °C

Procedure

To a stirred solution of Intermediate 235B (0.082 g, 0.543 mmol) in toluene (0.5 mL) was added TEA (0.076 mL, 0.543 mmol) and DPPA (0.074 mL, 0.339 mmol) and the reaction mass was warmed to 90° C. for 2 h. The reaction mixture was cooled to RT and to it was added a solution of Intermediate 185B (0.04 g, 0.136 mmol) in THF (0.5 mL) and stirred for 12 h. The reaction mixture was quenched with an aqueous solution of 10% NaHCO3 and extracted with ethyl acetate (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 235 as pale yellow solid (10 mg, 17% yield). HPLC retention times 1.40 and 1.41 min (Method E and L respectively). MS(ES): m/z=442 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85 (dd, J=7.28, 2.26 Hz, 1H), 7.68 (ddd, J=8.53, 4.77, 2.26 Hz, 1H), 7.43-7.49 (m, 1H), 7.35 (br. s., 1H), 7.30 (s, 1H), 7.20 (br. s., 1H), 6.04-6.34 (m, 1H), 4.75 (s, 2H), 4.14 (t, J=5.27 Hz, 2H), 3.86 (t, J=5.52 Hz, 2H), 2.28-2.35 (m, 3H), 2.09-2.19 (m, 2H), 1.71-1.97 (m, 2H).

Workup

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

Sources & evidence

ORD record
ord-988633d8322a463882d6cb73b7b4fdbc
Source dataset
uspto-grants-2016_03
Patent number
US09273058B2

Reaction notes

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