1,1,1,3,3,3-Hexafluoro-2-propanol → HCID 89682770, compound

HRID 2278255Notes

Reaction equation

HRID 2278255 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[C:38]([CH2:39][N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:37][CH:36]=[C:35]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[CH3:52])[N:34]=1>O.ClCCl>[CH3:32][C:33]1[C:38]([CH2:39][N:40]2[CH2:41][CH2:42][N:43]([C:5]([O:20][CH:15]([C:16]([F:19])([F:18])[F:17])[C:14]([F:22])([F:21])[F:13])=[O:11])[CH2:44][CH2:45]2)=[CH:37][CH:36]=[C:35]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[CH3:52])[N:34]=1

Participants

7

Reactant 4

HCID 135291,1,1,3,3,3-Hexafluoro-2-propanolHCID 81531DiisopropylethylamineHCID 94429TriphosgeneHCID 89676991HCID 89676991, compound

Product 1

HCID 89682770HCID 89682770, compoundYield 153.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

A 100 mL round-bottom flask, was charged with triphosgene (63.0 mg, 0.200 mmol, 0.30 equiv), dichloromethane (10 mL), 1,1,1,3,3,3-hexafluoropropan-2-ol (119 mg, 0.710 mmol, 1.00 equiv). N,N-Di-isopropylethylamine (174 mg, 1.35 mmol, 2.00 equiv) was added drop-wise. The resulting solution was stirred for 2 h at room temperature. 1-[[2-Methyl-6-(2-methylphenyl)pyridin-3-yl]methyl]piperazine (200 mg, 0.710 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature and then diluted with water (10 mL). The resulting mixture was extracted with dichloromethane (3×10 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (230 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 146.2 mg (43% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-methyl-6-(2-methylphenyl)pyridin-3-yl]methyl]piperazine-1-carboxylate as a off-white solid. 1H NMR 300 MHz (CDCl3) δ 7.62 (d, J=7.8 Hz, 1H), 7.37-7.40 (m, 1H), 7.31-7.35 (m, 3H), 7.19-7.28 (m, 1H), 5.72-5.80 (m, 1H), 3.56-3.59 (m, 6H), 2.64 (s, 3H), 2.51-2.56 (m, 4H), 2.36 (s, 3H). LCMS (ESI, m/z): 476 [M+H]+.

Workup

  1. stirringThe resulting solution was stirred overnight at room temperature
  2. extractionThe resulting mixture was extracted with dichloromethane (3×10 mL)
  3. dry with materialdried over anhydrous sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe crude product (230 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-efbf8fcd2f5b47308223aa399c4f6edf
Source dataset
uspto-grants-2015_09
Patent number
US09133148B2

Reaction notes

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