Diisopropylethylamine → 1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-ol

HRID 1915756Notes

Reaction equation

HRID 1915756 reaction equation
Cl[C:2]1[N:6]([CH2:7][CH:8]([F:10])[F:9])[N:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH:14]1[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>CCO>[F:9][CH:8]([F:10])[CH2:7][N:6]1[C:2]([N:14]2[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16][CH2:15]2)=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=[N:5]1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 5149746Azepan-4-olHCID 86679965HCID 86679965, compound

Product 1

HCID 866799681-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-olYield 62.1%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

A solution of 5-chloro-1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole (470 mg, 2.22 mmol), azepan-4-ol (281 mg, 2.44 mmol) and DIPEA (1 mL) in EtOH (3 mL) was heated at 155° C. in the microwave for 5 hr. The solvent was removed under reduced pressure and the residue purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give 1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-ol as a pale orange gum (400 mg). This gum (390 mg, 1.35 mmol) was dissolved in MeOH (25 mL) and treated with ammonium formate (340 mg, 5.38 mmol) and 10% palladium on carbon (50 mg). The mixture was heated at 85° C. for 4 hr. After standing at room temperature overnight more ammonium formate (205 mg, 3.25 mmol) and 10% palladium on carbon (50 mg) were added to the reaction mixture which was then heated at 85° C. for 1 hr. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was partitioned between DCM (30 mL) and water (20 mL). The organic layer was passed through a phase separation cartridge and the solvent was removed under reduced pressure to afford 1-(4-amino-1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)azepan-4-ol as an orange oil (265 mg, 42% over two steps). 1H NMR (400 MHz, CDCl3) δ 7.17 (s, 1H), 6.27-5.91 (m, 1H), 4.39-4.23 (m, 2H), 4.16-4.04 (m, 1H), 3.30-3.11 (m, 4H), 2.60 (br s, 3H), 2.55 (s, 2H), 2.08-1.81 (m, 3H), 1.80-1.71 (m, 1H).

Workup

  1. customThe solvent was removed under reduced pressure
  2. customthe residue purified by silica gel column chromatography (0-100% EtOAc/isohexane)

Sources & evidence

ORD record
ord-aad3426f1360458da4a58a0b33d49841
Source dataset
uspto-grants-2013_12
Patent number
US08614206B2

Reaction notes

Loading…