Dimethylamine, hydrochloride → N,N-dimethyl-3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]-benzamide

HRID 1017077Notes

Reaction equation

HRID 1017077 reaction equation
Cl.[CH3:2][NH:3][CH3:4].C[Al](C)C.O(C1C=C(N(CC2C=CC=C(OC(F)(F)C(F)F)C=2)CC(O)C(F)(F)F)C=CC=1)C1C=CC=CC=1.[O:44]([C:51]1[CH:52]=[C:53]([N:57]([CH2:65][C:66]2[CH:67]=[C:68]([CH:73]=[CH:74][CH:75]=2)[C:69](OC)=[O:70])[CH2:58][CH:59]([OH:64])[C:60]([F:63])([F:62])[F:61])[CH:54]=[CH:55][CH:56]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.CN([Al]CCl)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:2][N:3]([CH3:4])[C:69](=[O:70])[C:68]1[CH:73]=[CH:74][CH:75]=[C:66]([CH2:65][N:57]([C:53]2[CH:54]=[CH:55][CH:56]=[C:51]([O:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:52]=2)[CH2:58][CH:59]([OH:64])[C:60]([F:63])([F:62])[F:61])[CH:67]=1

Participants

8

Reactant 5

HCID 10473Dimethylamine, hydrochlorideHCID 98707043-((3-Phenoxyphenyl)((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)amino)-1,1,1-trifluoro-2-propanolHCID 10993963Methyl 3-(((3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino)methyl)benzoateHCID 16682925TrimethylaluminumHCID 57456614(N,N-dimethylamino)chloromethylaluminum

Product 1

HCID 23506078N,N-dimethyl-3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]-benzamideYield 91%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of N,N-dimethylamine hydrochloride (525 mg, 0.0064 mol) in 3.0 mL of toluene at −40° C. was added dropwise a 2.0 M solution of 20 trimethylaluminum in toluene (3:2 mL, 0.0064 mol) over 15 min. The reaction mixture was warmed to room temperature and stirred for 2 h. To a solution of methyl 3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzoate (209 mg, 0.00047 mol) from EX-612B in 2.5 mL of toluene at −10° C. was slowly added the (N,N-dimethylamino)-chloromethylaluminum reagent (850 μL, 0.00085 mol). The reaction mixture was warmed to room temperature then heated at 40° C. overnight. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate and quenched with 10% aqueous potassium hydrogen phosphate. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 2:3 ethyl acetate in hexane to afford 195 mg (91%) of the desired N,N-dimethyl-3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]-benzamide product as a pale yellow solid. Anal. calcd. for C25H25F3N2O3.0.5 H2O: C, 64.23; H, 5.61; N, 5.99. Found: C, 64.49; H, 5.77; N, 5.85. HRMS calcd. 459.1896 [M+H]+, found: 458.1887. 1H NMR (C6D6) δ7.01-6.95 (m, 3H), 6.92-6.87 (m, 5H), 6.79 (t, 1H), 6.46 (s, 1H), 6.37 (t, 2H), 4.91 (bs, 1H), 4.26 (s, 2H), 4.10 (bq, 1H), 3.84 (dd, 1H), 3.38 (dd, 1H), 2.53 (bs, 3H), 2.14 (bs, 3H). 19F NMR (C6D6) δ−78.69 (d, 3F).

Workup

  1. temperatureThe reaction mixture was warmed to room temperature
  2. temperaturethen heated at 40° C. overnight
  3. temperatureThe reaction mixture was cooled to room temperature
  4. customquenched with 10% aqueous potassium hydrogen phosphate
  5. dry with materialThe organic layer was dried over MgSO4
  6. concentrationconcentrated in vacuo
  7. customThe crude product was purified by column chromatography on silica gel eluting with 2:3 ethyl acetate in hexane

Sources & evidence

ORD record
ord-087c77e42c994f77ab216752e6ebc5be
Source dataset
uspto-grants-2002_11
Patent number
US06476075B1

Reaction notes

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