1,1,1,3,3,3-Hexafluoro-2-propanol → HCID 89677109, compound

HRID 2278292Notes

Reaction equation

HRID 2278292 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][N:33]([CH3:55])[C:34](=[O:54])[C:35]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:37][C:36]=1[CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>ClCCl.O>[CH3:32][N:33]([CH3:55])[C:34]([C:35]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:37][C:36]=1[CH2:47][N:48]1[CH2:53][CH2:52][N:51]([C:5]([O:20][CH:15]([C:16]([F:19])([F:18])[F:17])[C:14]([F:22])([F:21])[F:13])=[O:11])[CH2:50][CH2:49]1)=[O:54]

Participants

7

Reactant 4

HCID 135291,1,1,3,3,3-Hexafluoro-2-propanolHCID 81531DiisopropylethylamineHCID 94429TriphosgeneHCID 89677150HCID 89677150, compound

Product 1

HCID 89677109HCID 89677109, compoundYield 94.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

A 100 mL round-bottom flask was charged with triphosgene (55.0 mg, 0.190 mmol, 0.30 equiv) in dichloromethane (10 mL). 1,1,1,3,3,3-Hexafluoropropan-2-ol (104 mg, 0.620 mmol, 1.00 equiv) and N,N-diisopropylethylamine (152 mg, 1.18 mmol, 1.90 equiv) were added dropwise. The mixture was stirred for 30 min at room temperature. N,N-Dimethyl-5-phenyl-2-(piperazin-1-ylmethyl)benzamide (200 mg, 0.620 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with water (20 mL), extracted with dichloromethane (3×20 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product (240 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 93.2 mg (28% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-(dimethylcarbamoyl)-4-phenylphenyl]methyl]piperazine-1-carboxylate as light yellow oil. 1H NMR 300 MHz (CDCl3) δ 7.36-7.81 (m, 8H), 5.70-5.80 (m, 1H), 3.41-3.67 (m, 4H), 3.03-3.30 (m, 4H), 2.84-3.02 (m, 4H), 2.40-2.66 (m, 4H). LCMS (ESI, m/z): 518 [M+H]+.

Workup

  1. stirringThe resulting solution was stirred overnight at room temperature
  2. extractionextracted with dichloromethane (3×20 mL)
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe crude product (240 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-4ad0d8cc607547099ec7a8ae4c5b0d68
Source dataset
uspto-grants-2015_09
Patent number
US09133148B2

Reaction notes

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