Tetrahydrofuran → 2-(3-Chloro-4-fluorophenyl)-N5-(1-(cyanomethyl)cyclobutyl)-6,7-dihydro pyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide

HRID 920736Notes

Reaction equation

HRID 920736 reaction equation
[C:1]([CH2:3][C:4]1(C(O)=O)[CH2:7][CH2:6][CH2:5]1)#[N:2].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:4]4([CH2:3][C:1]#[N:2])[CH2:5][CH2:6][CH2:7]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 1054280091-(Cyanomethyl)cyclobutane-1-carboxylic acidHCID 1180616272-(3-Chloro-4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

Product 1

HCID 1180620032-(3-Chloro-4-fluorophenyl)-N5-(1-(cyanomethyl)cyclobutyl)-6,7-dihydro pyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamideYield 32%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
90 °C

Procedure

To a stirred solution of Intermediate 220C (0.020 g, 0.145 mmol) in toluene (0.5 mL) was added TEA (0.081 mL, 0.578 mmol), DPPA (0.078 mL, 0.361 mmol) and the reaction mixture was warmed to 90° C. and stirred for 2 h. The reaction mixture was cooled to RT and to it was added a solution of Intermediate 185B (0.040 g, 0.145 mmol) in THF (0.5 mL) and stirred at RT for 16 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 220 as a pale yellow solid (20 mg, 32%). HPLC retention times 1.21 min. and 1.21 min. (Method E and L respectively). MS(ES): m/z=431 [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), 7.46 (t, J=9.04 Hz, 1H), 7.34 (br. s., 1H), 7.29 (s, 1H), 7.18 (br. s., 1H), 4.74 (s, 2H), 4.14 (t, J=5.27 Hz, 2H), 3.86 (t, J=5.27 Hz, 2H), 3.11 (s, 2H), 2.17-2.27 (m, 2H), 2.02-2.11 (m, 2H), 1.78-1.91 (m, 2H).

Workup

  1. temperatureThe reaction mixture was cooled to RT and to it
  2. stirringstirred at RT for 16 h
  3. customThe reaction mixture was quenched with a 10% aqueous solution of NaHCO3
  4. extractionextracted with EtOAc (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-9e26b578a2674e02875dcf50befa0409
Source dataset
uspto-grants-2016_03
Patent number
US09273058B2

Reaction notes

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