Acetic Acid → 3-[[3-(Methoxymethyl)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol

HRID 48035

Reaction equation

HRID 48035 reaction equation
[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[F:11][C:12]([F:25])([O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)[CH:13]([F:15])[F:14].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[F:44][C:45]([F:50])([F:49])[CH:46]1[O:48][CH2:47]1>ClC(Cl)C.C(#N)C.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([N:7]([CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([O:16][C:12]([F:25])([F:11])[CH:13]([F:15])[F:14])[CH:18]=2)[CH2:47][CH:46]([OH:48])[C:45]([F:50])([F:49])[F:44])[CH:8]=[CH:9][CH:10]=1

Participants

9

Reactant 5

HCID 176Acetic AcidHCID 118803Benzaldehyde, 3-(1,1,2,2-tetrafluoroethoxy)-HCID 5207692-(Trifluoromethyl)oxiraneHCID 5049666Sodium triacetoxyborohydrideHCID 130420323-(Methoxymethyl)aniline

Product 1

HCID 235060003-[[3-(Methoxymethyl)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanolYield 97%

Reagents, catalysts & solvents 3

HCID 2733225Ytterbium triflateCatalystHCID 6342AcetonitrileSolventHCID 63651,1-DichloroethaneSolvent

Procedure

Ex-514C) The 3-(methoxymethyl)aniline (1.85 g, 13.51 mmol) product from EX-514B and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (3 g, 13.5 mmol) were dissolved in 25 mL of dichloroethane and acetic acid (0.85 mL, 14.8 mmol), then solid NaBH(OAc)3 (3.73 g, 17.6 mmol) was added. The mixture was stirred at room temperature for 48 hours, then quenched with aqueous saturated sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed with brine, then dried over MgSO4, and concentrated in vacuo to give 4.27 g (12.4 mmol) of crude product. The crude product and 1,1,1-trifluoro-2,3-epoxypropane (1.2 mL, 13.7 mmol) were dissolved in 20 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0.77 g, 1.24 mmol) was added, and the stirred solution was warmed to 50° C. for 18 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, then dried over MgSO4, and concentrated in vacuo to give 5.96 g (97%) of the desired 3-[[3-(methoxymethyl)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a brown oil. The crude product was greater than 95% pure by reverse phase HPLC analysis and was used without further purification. HRMS calcd. for C20H21F7NO3: 456.1410 [M+H]+, found: 456.1409. 1H NMR (CDCl3) δ3.3 (s, 3H), 3.6 (dd, 1H), 3.9 (dd, 1H), 4.3 (m, 1H), 4.4 (s, 2H), 4.7 (m, 2H), 5.9 (tt, 1H), 6.6-6.8 (m, 3H), 7.1-7.2 (m, 4H), 7.3 (t, 1H).

Workup

  1. customquenched with aqueous saturated sodium bicarbonate
  2. additiondiluted with ethyl acetate
  3. washThe organic layer was washed with brine
  4. dry with materialdried over MgSO4
  5. concentrationconcentrated in vacuo
  6. customto give 4.27 g (12.4 mmol) of crude product
  7. temperaturethe stirred solution was warmed to 50° C. for 18 hours
  8. customThe reaction was quenched with water
  9. extractionextracted with ethyl acetate
  10. washThe organic layer was washed with brine
  11. dry with materialdried over MgSO4
  12. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-0885deb558664ed8afffd41b2288485f
Source dataset
uspto-grants-2004_03
Patent number
US06699898B2

Linked notes

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