1,1,1,3,3,3-Hexafluoro-2-propanol → 1,1,1,3,3,3-Hexafluoropropan-2-yl 4-[[2-methyl-4-(3-methylphenyl)phenyl]methyl]piperazine-1-carboxylate

HRID 2278264Notes

Reaction equation

HRID 2278264 reaction equation
ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:22])([F:21])[CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)C(C)C)(C)C.[CH3:32][C:33]1[CH:38]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[CH:40]=2)[CH:36]=[CH:35][C:34]=1[CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>O.ClCCl>[CH3:32][C:33]1[CH:38]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[CH:40]=2)[CH:36]=[CH:35][C:34]=1[CH2:46][N:47]1[CH2:48][CH2:49][N:50]([C:5]([O:20][CH:15]([C:16]([F:19])([F:18])[F:17])[C:14]([F:22])([F:21])[F:13])=[O:11])[CH2:51][CH2:52]1

Participants

7

Reactant 4

HCID 135291,1,1,3,3,3-Hexafluoro-2-propanolHCID 81531DiisopropylethylamineHCID 94429TriphosgeneHCID 896771541-[[2-Methyl-4-(3-methylphenyl)phenyl]methyl]piperazine

Product 1

HCID 896827401,1,1,3,3,3-Hexafluoropropan-2-yl 4-[[2-methyl-4-(3-methylphenyl)phenyl]methyl]piperazine-1-carboxylateYield 55%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

A 100 mL round-bottom flask was charged with triphosgene (160 mg, 0.540 mmol, 0.30 equiv), dichloromethane (20 mL). 1,1,1,3,3,3-Hexafluoropropan-2-ol (302 mg, 1.80 mmol, 1.00 equiv) and N,N-diisopropylethylamine (441 mg, 3.41 mmol, 1.90 equiv) were added. The resulting solution was stirred for 2 h at room temperature. 1-[[2-methyl-4-(3-methylphenyl)phenyl]methyl]piperazine (500 mg, 1.78 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with water (50 mL), extracted with dichloromethane (3×40 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product (250 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% CH3CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 141 mg (16% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-methyl-4-(3-methylphenyl)phenyl]methyl]piperazine-1-carboxylate as colorless oil. 1H NMR 400 MHz (CDCl3) δ 7.30-7.42 (m, 6H), 7.18 (d, J=7.2 Hz, 1H), 5.76-5.82 (m, 1H), 3.55-3.58 (m, 6H), 2.45-2.53 (m, 10H). LCMS (ESI, m/z): 475 [M+H]+.

Workup

  1. stirringThe resulting solution was stirred overnight at room temperature
  2. extractionextracted with dichloromethane (3×40 mL)
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe crude product (250 mg) was purified by preparative HPLC
  7. wait20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min
  8. waitto 100% CH3CN over 0.1 min
  9. waitholding at 100% CH3CN for 1.9 min
  10. waitreducing to 20% CH3CN over 0.1 min
  11. waitholding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph
  12. customPurification

Sources & evidence

ORD record
ord-1aea9dd4fda7423d84b04e064aa09795
Source dataset
uspto-grants-2015_09
Patent number
US09133148B2

Reaction notes

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