Diisopropylethylamine → (R)-N-(1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methyl-5-(trifluoromethyl)oxazole-4-carboxamide

HRID 238862Notes

Reaction equation

HRID 238862 reaction equation
[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C@:12]([C:21]3[CH:26]=[C:25]([O:27][C:28]([F:33])([F:32])[CH:29]([F:31])[F:30])[CH:24]=[C:23]([F:34])[CH:22]=3)([NH2:20])[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=[CH:9][C:10]=2[F:11])[CH2:3][CH2:2]1.[CH3:35][C:36]1[O:37][C:38]([C:44]([F:47])([F:46])[F:45])=[C:39]([C:41](O)=[O:42])[N:40]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C@@:12]([NH:20][C:41]([C:39]3[N:40]=[C:36]([CH3:35])[O:37][C:38]=3[C:44]([F:47])([F:45])[F:46])=[O:42])([C:21]3[CH:26]=[C:25]([O:27][C:28]([F:33])([F:32])[CH:29]([F:31])[F:30])[CH:24]=[C:23]([F:34])[CH:22]=3)[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=[CH:9][C:10]=2[F:11])[CH2:2][CH2:3]1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733179PyBroPHCID 27756512-methyl-5-(trifluoromethyl)-1,3-oxazole-4-carboxylic AcidHCID 59459264(R)-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine

Product 1

HCID 59459256(R)-N-(1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methyl-5-(trifluoromethyl)oxazole-4-carboxamideYield 70%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of (R)-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine, prepared as described in Procedure 109, 110, 111, 112, 113, 114, 161, (24 mg, 0.05 mmol) in CH2Cl2 (0.5 mL) was added 2-methyl-5(trifluoromethyl)-oxazole-4-carboxylic acid (12 mg, 0.06 mmol), followed by PyBrOP (28 mg, 0.06 mmol) and iPr2NEt (9 mg, 0.065 mmol). The reaction mixture was stirred at rt for 72 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep HPLC (Phenomenex Luna 5μ, 30×100 mm, eluting with 10%-90% MeOH/H2O containing 0.1% TFA, gradient time 10 min, flow rate 40 mL/min) to yield (R)—N-(1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methyl-5-(trifluoromethyl)oxazole-4-carboxamide (Example 347) as a white solid (23 mg, 70% yield). HPLC: RT=2.18 min [M+H] 659.5 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 7.79, s, 1H, 7.10-7.20, m, 3H, 6.90-7.03, m, 5H, 6.70, s, 1H, 6.68, s, 1H, 6.55-6.58, m, 1H, 5.74-6.00, t, J=52; 4.15, 4.19, d, J=16, 1H, 3.66-3.69, d, J=12, 1H, 3.51-3.54, m, 1H, 0.73-0.80, m, 1H, 0.61-0.69, m, 2H, 0.55-0.60, m, 1H.

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. customthe residue was purified by prep HPLC (Phenomenex Luna 5μ, 30×100 mm, eluting with 10%-90% MeOH/H2O containing 0.1% TFA, gradient time 10 min, flow rate 40 mL/min)

Sources & evidence

ORD record
ord-2bf2de50276e426e94525033edbad25e
Source dataset
uspto-grants-2014_02
Patent number
US08642576B2

Reaction notes

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