Diisopropylethylamine → tert-Butyl 4-(3-fluoro-5-methoxy-4-nitrophenyl)piperazine-1-carboxylate

HRID 871857Notes

Reaction equation

HRID 871857 reaction equation
[F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[N+:11]([O-:13])=[O:12].[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[N+:11]([O-:13])=[O:12]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 143452tert-Butyl piperazine-1-carboxylateHCID 103301291,5-Difluoro-3-methoxy-2-nitrobenzene

Product 1

HCID 86673135tert-Butyl 4-(3-fluoro-5-methoxy-4-nitrophenyl)piperazine-1-carboxylateYield 21.2%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of 2.48 g (13.1 mmol) of the product prepared in step 10.1 in 26 mL of acetonitrile are added 2.43 g (13.1 mmol) of tert-butyl piperazinecarboxylate and 3.36 mL (19.65 mmol) of diisopropylethylamine. The reaction mixture is heated at 90°C. for 20 hours. It is diluted with ethyl acetate and washed with water and then with saturated aqueous NaCl solution. The crude solid is purified by chromatography on a column of silica, eluting with a cyclohexane/ethyl acetate gradient (85/15 to 50/50). A 3.25 g fraction predominantly containing the regioisomer tert-butyl 4-(5-fluoro-3-methoxy-2-nitrophenyl)piperazine-1-carboxylicate is isolated. An impure secondary fraction is purified again on a column of silica, eluting with a dichloromethane/ethyl acetate gradient (96/4 to 94/6). 0.985 g of expected product is finally obtained in the form of a yellow solid. Yield=21%.

Workup

  1. washwashed with water
  2. customThe crude solid is purified by chromatography on a column of silica
  3. washeluting with a cyclohexane/ethyl acetate gradient (85/15 to 50/50)
  4. additionA 3.25 g fraction predominantly containing the regioisomer tert-butyl 4-(5-fluoro-3-methoxy-2-nitrophenyl)piperazine-1-carboxylicate
  5. customis isolated
  6. customAn impure secondary fraction is purified again on a column of silica
  7. washeluting with a dichloromethane/ethyl acetate gradient (96/4 to 94/6)

Sources & evidence

ORD record
ord-caaa639eaa9244d0a55ed3dce422f8b8
Source dataset
uspto-grants-2015_03
Patent number
US08975250B2

Reaction notes

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