N-methyl-2-pyrrolidone → HCID 71227465, compound

HRID 715529Notes

Reaction equation

HRID 715529 reaction equation
[CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[N:4]1)[CH3:2].[Li]CCCC.[CH3:22][C@:23]1([CH2:31][N:32]2[C:36]3[CH:37]=[C:38]([C:41]#[N:42])[CH:39]=[CH:40][C:35]=3[N:34]=[CH:33]2)CCC[C@:25]2(OC2)[CH2:24]1.CN1C(=O)CCC1>C1COCC1.O>[CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([N:9]2[CH2:13][C@@:12]3([CH2:15][CH2:25][CH2:24][C@@:23]([CH2:31][N:32]4[C:36]5[CH:37]=[C:38]([C:41]#[N:42])[CH:39]=[CH:40][C:35]=5[N:34]=[CH:33]4)([CH3:22])[CH2:14]3)[O:11][C:10]2=[O:16])[CH:5]=[N:4]1)[CH3:2]

Participants

7

Reactant 4

HCID 13387N-methyl-2-pyrrolidoneHCID 86716577((3S,5S)-5-methyl-1-oxaspiro[2.5]octan-5-ylmethyl)-1H-benzo[d]imidazole-6-carbonitrileHCID 131734098HCID 131734098, compoundHCID 178418339Butyllithium

Product 1

HCID 71227465HCID 71227465, compoundYield 38.9%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of 1-ethyl-5-methyl-1H-pyrazol-4-amine, 2 hydrochloride (0.5 g, 2.52 mmol), Boc2O (0.703 ml, 3.03 mmol), TEA (1.055 mL, 7.57 mmol) and DMAP (10 mg, 0.082 mmol) in DCM (18.74 mL) was stirred at RT for 16 h. The mixture was then extracted with DCM, dried over Na2SO4 and filtered. The filtrate was concentrated and purified via silica gel chromatography (ISCO, 40 g column; 0-5% MeOH/DCM) to give tert-butyl (1-ethyl-5-methyl-1H-pyrazol-4-yl)carbamate as brown oil (300 mg, 52.8% yield). To a solution of tert-butyl (1-ethyl-5-methyl-1H-pyrazol-4-yl)carbamate (0.162 g, 0.719 mmol) in THF (1 mL) at −78° C. under N2 was added n-BuLi (2.5M in hexane) (0.27 ml, 0.675 mmol) dropwise. The mixture was allowed to warm up to RT and stirred for 20 min. 1-{[(3S,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile (0.15 g, 0.533 mmol) was then added followed by NMP (0.5 mL). The solution was then heated at 70° C. for 16 h. Water was then added to the reaction mixture and extracted with EtOAc. The organic layer was concentrated and purified via HPLC to give 1-(((5S,7S)-3-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile as a white solid (89.6 mg, 38.9% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.38 (s, 1H), 7.83 (d, J=8.28 Hz, 1H), 7.59 (dd, J=1.51, 8.28 Hz, 1H), 7.41 (s, 1H), 4.16 (br. s., 2H), 4.03 (q, J=7.03 Hz, 2H), 3.54 (s, 2H), 2.14 (s, 3H), 1.95 (d, J=14.0 Hz, 1H), 1.86 (d, J=14.31 Hz, 1H), 1.61 (d, J=13.55 Hz, 3H), 1.31-1.51 (m, 3H), 1.28 (t, 3H), 1.06 (s, 3H). MS (m/z) 433.3 (M+H+).

Workup

  1. temperatureThe solution was then heated at 70° C. for 16 h
  2. extractionextracted with EtOAc
  3. concentrationThe organic layer was concentrated
  4. custompurified via HPLC

Sources & evidence

ORD record
ord-a8adcd2cc18b4e44bc07c10ca4628185
Source dataset
uspto-grants-2015_11
Patent number
US09187464B2

Reaction notes

Loading…