Triethylamine → HCID 45101529, compound

HRID 547578Notes

Reaction equation

HRID 547578 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C(Cl)(=O)C(Cl)=O.[CH2:22]([S:24]([CH2:27][CH2:28][NH:29][C@@H:30]([C:32]1[N:33]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH2:50][C:51]([F:54])([F:53])[F:52])=[CH:45][CH:44]=2)[C:34](=[O:42])[C:35]2[CH:41]=[CH:40][CH:39]=[N:38][C:36]=2[N:37]=1)[CH3:31])(=[O:26])=[O:25])[CH3:23].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C.ClCCl>[CH2:22]([S:24]([CH2:27][CH2:28][N:29]([C@@H:30]([C:32]1[N:33]([C:43]2[CH:44]=[CH:45][C:46]([O:49][CH2:50][C:51]([F:52])([F:53])[F:54])=[CH:47][CH:48]=2)[C:34](=[O:42])[C:35]2[CH:41]=[CH:40][CH:39]=[N:38][C:36]=2[N:37]=1)[CH3:31])[C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:4]=1)(=[O:26])=[O:25])[CH3:23]

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 516892Sodium BicarbonateHCID 27375934-Fluoro-3-(trifluoromethyl)phenylacetic acidHCID 58617390HCID 58617390, compound

Product 1

HCID 45101529HCID 45101529, compound

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent2×

Procedure

The acid chloride (4-fluoro-3-trifluoromethyl-phenyl)acetyl chloride was prepared by addition of several drops of DMF to an ice-cold solution of 2.06 g (4-fluoro-3-trifluoromethyl-phenyl)acetic acid (9.27 mmol, 1.70 equiv.) and 0.81 mL oxalyl chloride (9.27 mmol, 1.70 equiv.) dissolved in 15 mL dichloromethane. Gas evolution ensued and the reaction was equilibrated to room temperature and stirred for 2 h until gas evolution ceased. This solution was added dropwise over 15 min. to a solution of 2.6 g B2 (5.37 mmol, 1.00 equiv.) and 2.24 mL triethylamine (16.1 mmol, 3.00 equiv.) dissolved in 20 mL dichloromethane cooled by an acetone-dry ice bath. The resulting mixture was stirred at low temperature for 20 min. then poured into saturated aqueous sodium bicarbonate. The organic separation was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a glassy solid. The product was purified by chromatography on silica gel, eluting with a gradient of 50% ethyl acetate in hexane to 100% ethyl acetate. The chromatographed product was then recrystallized from methyl tert-butyl ether to afford 2 as colorless crystals, m.p.=157-159° C. 1H NMR (400 MHz; CDCl3; T=300 K) {mixture of S-cis:S-trans amide rotamers in ca. 2.3:1 ratio} δ 1.20 (t, J=7.6 Hz, 3H), 1.46 (t, J=7.2 Hz, 6.5H), 1.46 (d, J=7.2 Hz, 6.5H), 2.48 (d, J=16 Hz, 1H), 2.92 (ddd, J=2.8, 7.6, 16.0 Hz, 2H), 2.94 (d, J=16 Hz, 1H), 3.13 (ddd, J=3.6, 7.2, 14.8 Hz, 4.6H), 3.22 (dd, J=6.8, 6.8 Hz, 2H), 3.50 (ddd, J=5.2, 10.6, 13.3 Hz, 2.3H), 3.67 (ddd, J=8.0, 8.0, 13.3 Hz, 1H), 3.84 (s, 4.6H), 3.90 (ddd, J=4.8, 10, 14.8 Hz, 2.3H), 4.02 (ddd, J=8.0, 8.0, 13.3 Hz, 1H), 4.06-4.27 (m, 4.6H), 4.42 (qt, J=8 Hz, 6.6H), 5.01 (qt, J=6.8 Hz, 1H), 5.16 (qt, J=7.2 Hz, 2.3H), 7.09-7.19 (m, 10H), 7.21-7.28 (m, 5H), 7.33-7.50 (m, 8.9H), 7.53 (dd, J=4.6, 9.1 Hz, 1H), 7.63-7.68 (m, 2.3H), 8.58 (dd, J=2.0, 8.0 Hz, 2.3H), 8.61 (dd, J=2.0, 8.0 Hz, 1H), 8.96 (dd, J=2.0, 4.4 Hz, 2.3H), 9.06 (dd, J=2.0, 4.8 Hz, 1H) ppm. MS (ESI+) m/z=688.9 [M+H]+. Analytical calculated: 52.33% C, 3.95% H, 19.31% F, 8.14% N. Found: 52.29% C, 3.97% H, 19.40% F, 8.12% N.

Workup

  1. customwas equilibrated to room temperature
  2. temperaturecooled by an acetone-dry ice bath
  3. stirringThe resulting mixture was stirred at low temperature for 20 min.
  4. customThe organic separation
  5. washwas washed with brine
  6. dry with materialdried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customto afford a glassy solid
  10. customThe product was purified by chromatography on silica gel
  11. washeluting with a gradient of 50% ethyl acetate in hexane to 100% ethyl acetate
  12. customThe chromatographed product was then recrystallized from methyl tert-butyl ether

Sources & evidence

ORD record
ord-488d13f5c96745b48fcd66909155ea0e
Source dataset
uspto-grants-2011_05
Patent number
US07939538B2

Reaction notes

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