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 1712827Notes

Reaction equation

HRID 1712827 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-aa0343a0d92648469a7f7ca3018ff440
Source dataset
uspto-grants-2010_09
Patent number
US07790770B2

Reaction notes

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