1,1,1,3,3,3-Hexafluoro-2-propanol → HCID 71657503, compound

HRID 2278236Notes

Reaction equation

HRID 2278236 reaction equation
Cl[C:2](Cl)([O:4]C(=O)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.[Cl:32][C:33]1[CH:34]=[C:35]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[CH:36]=[CH:37][C:38]=1[CH2:39][N:40]1[CH2:45][CH2:44][NH:43][C@@H:42]([CH3:46])[CH2:41]1>O.ClCCl>[Cl:32][C:33]1[CH:34]=[C:35]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[CH:36]=[CH:37][C:38]=1[CH2:39][N:40]1[CH2:45][CH2:44][N:43]([C:2]([O:20][CH:15]([C:16]([F:19])([F:18])[F:17])[C:14]([F:22])([F:21])[F:13])=[O:4])[C@@H:42]([CH3:46])[CH2:41]1

Participants

7

Reactant 4

HCID 135291,1,1,3,3,3-Hexafluoro-2-propanolHCID 81531DiisopropylethylamineHCID 94429TriphosgeneHCID 89677139HCID 89677139, compound

Product 1

HCID 71657503HCID 71657503, compoundYield 53%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

A 100 mL round-bottom flask was charged with dichloromethane (20 mL), triphosgene (86.0 mg, 0.290 mmol, 0.300 equiv). 1,1,1,3,3,3-Hexafluoropropan-2-ol (163 mg, 0.970 mmol, 1.00 equiv) and N,N-diisopropylethylamine (238 mg, 1.84 mmol, 1.90 equiv) were added. The mixture was stirred for 2 h at room temperature. 4-(3-Chloro-4-[[(3S)-3-methylpiperazin-1-yl]methyl]phenyl)morpholine (300 mg, 0.970 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (20 mL), extracted with dichloromethane (3×15 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product (180 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 77.5 mg (15% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl(2S)-4-[[2-chloro-4-(morpholin-4-yl)phenyl]methyl]-2-methylpiperazine-1-carboxylate as light yellow oil. 1H NMR 400 MHz (CDCl3) δ 7.28-7.30 (m, 1H), 6.88 (d, J=2.4 Hz, 1H), 6.77-6.80 (m, 1H), 5.73-5.79 (m, 1H), 4.26 (br, 1H), 3.84 (t, J=4.8 Hz, 5H), 3.48-3.56 (m, 2H), 3.25 (br, 1H), 3.15 (t, J=5.2 Hz, 4H), 2.80-2.82 (m, 1H), 2.66 (d, J=10.8 Hz, 1H), 2.28-2.31 (m, 1H), 2.10-2.16 (m, 1H), 1.30 (d, J=6.8 Hz, 3H). LCMS (ESI, m/z): 504 [M+H]+.

Workup

  1. stirringThe resulting solution was stirred overnight at room temperature
  2. extractionextracted with dichloromethane (3×15 mL)
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe crude product (180 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-451040cac543498dab3e4ca271e7084e
Source dataset
uspto-grants-2015_09
Patent number
US09133148B2

Reaction notes

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