Acetic Acid → tert-Butyl 4-(4-fluoro-2-(2-hydroxyethylthio)-5-nitrophenylamino)piperidine-1-carboxylate

HRID 424594Notes

Reaction equation

HRID 424594 reaction equation
[NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[S:12][CH2:13][CH2:14][OH:15].O=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[F:11][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]([NH:1][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[C:3]([S:12][CH2:13][CH2:14][OH:15])[CH:4]=1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylate3×HCID 5049666Sodium triacetoxyborohydride3×HCID 591440992-(2-Amino-5-fluoro-4-nitrophenylthio)ethanol

Product 1

HCID 59144085tert-Butyl 4-(4-fluoro-2-(2-hydroxyethylthio)-5-nitrophenylamino)piperidine-1-carboxylateYield 91.4%

Reagents, catalysts & solvents 1

HCID 63651,1-DichloroethaneSolvent

Procedure

To a stirred solution of 2-(2-amino-5-fluoro-4-nitrophenylthio)ethanol (434 mg, 1.869 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (372 mg, 1.869 mmol) in dichloroethane (10 mL) and acetic acid (0.321 mL, 5.61 mmol) was added sodium triacetoxyborohydride (594 mg, 2.80 mmol). The resulting mixture was stirred at room temperature. After 1 hour, additional tert-butyl 4-oxopiperidine-1-carboxylate (372 mg, 1.869 mmol) was added, followed by additional sodium triacetoxyborohydride (594 mg, 2.80 mmol). After a further 3 hours, more tert-butyl 4-oxopiperidine-1-carboxylate (372 mg, 1.869 mmol) was added followed by more sodium triacetoxyborohydride (594 mg, 2.80 mmol). The reaction mixture was stirred overnight. The mixture was then quenched with 1 N NaOH (10 mL), water (20 mL), and saturated sodium carbonate (20 mL). The organic products were then extracted with dichloromethane (3×20 mL). The combined organics were dried, filtered, concentrated, and then chromatographed using 1:3 ethyl acetate:hexanes on silica gel to give the desired product (710 mg, 91%). 1H NMR (DMSO-d6) δ 7.45 (d, J=12.0 Hz, 1H), 7.23 (d, J=6.6 Hz, 1H), 5.08 (t, J=5.4 Hz, 1H), 5.02 (d, J=8.1 Hz, 1H), 3.96-3.84 (m, 2H), 3.69-3.55 (m, 5H), 2.99-2.83 (m, 2H), 1.92-1.83 (m, 2H), 1.45-1.18 (m, 11H); ESI-MS (m/z, %): 360 (100), 128 (30).

Workup

  1. waitAfter a further 3 hours
  2. stirringThe reaction mixture was stirred overnight
  3. customThe mixture was then quenched with 1 N NaOH (10 mL), water (20 mL), and saturated sodium carbonate (20 mL)
  4. extractionThe organic products were then extracted with dichloromethane (3×20 mL)
  5. customThe combined organics were dried
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customchromatographed

Sources & evidence

ORD record
ord-099421b9e7eb4b4ab814bb7de8a996ef
Source dataset
uspto-grants-2012_01
Patent number
US08106043B2

Reaction notes

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