1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → (S)-4-Fluoro-N-(2-hydroxy-2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(trifluoromethyl)benzamide

HRID 238823Notes

Reaction equation

HRID 238823 reaction equation
[NH2:1][C:2]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=1)[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][C:35]=1[C:43]([F:46])([F:45])[F:44].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.C(#N)C.CCOC(C)=O>[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH:1][C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:20])([F:21])[F:19])[CH:12]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:30])([F:31])[F:32])[CH:23]=2)[C@@H:3]([OH:4])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:39])=[CH:36][C:35]=1[C:43]([F:44])([F:45])[F:46]

Participants

8

Reactant 4

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 5222684-Fluoro-3-(trifluoromethyl)benzoic acidHCID 59459057HCID 59459057, compound

Product 1

HCID 59458452(S)-4-Fluoro-N-(2-hydroxy-2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(trifluoromethyl)benzamideYield 15%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of (S)-2-amino-1-phenyl-2,2-bis(3-(trifluoromethoxy)phenyl)ethanol (44 mg, 0.096 mmol), 4-fluoro-3-(trifluoromethyl)benzoic acid (20 mg, 0.096 mmol), EDCI (28 mg, 0.14 mmol), HOBT (14 mg, 0.096 mmol) and a catalytic amount of DMAP in acetonitrile (3 mL) was stirred for 24 h at rt. The reaction mixture was diluted with EtOAc and washed successively with 1 N HCl, 1 N NaOH, sat. NaCl, dried over MgSO4, filtered and concentrated. The residue was purified by preparative HPLC Shimadzu-YMC Sunfire 5 μcolumn, 30×100 mm eluting with 50-100% MeOH (90% in H2O, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm. (S)-4-Fluoro-N-(2-hydroxy-2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(trifluoromethyl)benzamide (Example 311) was isolated as a colorless film (10 mg, 15% yield). HPLC: RT=4.143 minutes (Phenomenex Luna C18 5 u column eluting with 10-90% aqueous methanol containing 0.1% phosphoric acid over a 4 minute gradient monitoring at 220 nm). LCMS: [M+H] 648.0 (Phenomenex Luna C18 column, 4.6×30 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 8.23 (m, 1H), 7.37-6.9 (m, 15H), 5.41 (s, 1H).

Workup

  1. washwashed successively with 1 N HCl, 1 N NaOH, sat. NaCl
  2. dry with materialdried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue was purified by preparative HPLC Shimadzu-YMC Sunfire 5 μcolumn, 30×100 mm
  6. washeluting with 50-100% MeOH (90% in H2O, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm

Sources & evidence

ORD record
ord-58284bd33424422790adc0c30f4e19a2
Source dataset
uspto-grants-2014_02
Patent number
US08642576B2

Reaction notes

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