Trifluoroacetic acid → Trifluoroacetic acid

HRID 1171613Notes

Reaction equation

HRID 1171613 reaction equation
Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:20]=1)[C:6]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH3:10])=[O:7].[OH:27][CH2:28][C:29]([NH:38]C(=O)OC(C)(C)C)([CH2:36][OH:37])[CH2:30][C:31]1[CH:35]=[CH:34][S:33][CH:32]=1.C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.[C:60]([OH:66])([C:62]([F:65])([F:64])[F:63])=[O:61]>C(Cl)Cl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[NH2:38][C:29]([CH2:30][C:31]1[CH:35]=[CH:34][S:33][CH:32]=1)([CH2:28][OH:27])[CH2:36][O:37][CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:20]=1)[C:6]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH3:10])=[O:7].[C:60]([OH:66])([C:62]([F:65])([F:64])[F:63])=[O:61]

Participants

8

Reactant 4

HCID 6422Trifluoroacetic acidHCID 685102,6-Di-tert-butylpyridine2×HCID 16094314HCID 16094314, compoundHCID 59553961HCID 59553961, compound

Product 2

HCID 6422Trifluoroacetic acidHCID 59553979HCID 59553979, compound

Reagents, catalysts & solvents 2

HCID 76223Silver(I) trifluoromethanesulfonateCatalystHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of intermediate A 3-(bromomethyl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide (50 mg, 0.11 mmol) in 1 mL CH2Cl2 cooled to 0° C. was added intermediate m tert-butyl 2-hydroxy-1-(hydroxymethyl)-1-(thien-3-ylmethyl)ethylcarbamate (81 mg, 0.28 mmol), silver triflate (72 mg, 0.28 mmol) and 2,6-ditert-butylpyridine (76 μL, 0.34 mmol). The reaction mixture was stirred at 0° C. for 40 min and purified by flash chromatography (20 g silica, 30→80% EtOAc/hexanes) and by preparative HPLC (5% to 95% CH3CN in water containing 0.1% TFA, C18 PRO YMC 20×150 mm) to afford tert-butyl 2-({3-({[(1R)-1-(4-fluorophenyl)ethyl]amino}carbonyl)-5-[methyl(methylsulfonyl)amino]benzyl}oxy)-1-(hydroxymethyl)-1-(thien-3-ylmethyl) contaminated with 2,6-ditert-butylpyridine. Treatment with 10% TFA in CH2Cl2 for 30 min, followed by concentration under a stream of nitrogen, and purification by preparative HPLC (5% to 95% CH3CN in water containing 0.1% TFA, C18 PRO YMC 20×150 mm) afforded 3-{[2-amino-3-hydroxy-2-(thien-3-ylmethyl)propoxy]methyl}-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide as a TFA salt. 1H NMR (400 MHz, d4-MeOH) δ 8.86 (d, J=7.9 Hz, 1H), 7.83 (s, 1H), 7.80 (s, 1H), 7.65 (s, 1H), 7.48-7.36 (m, 3H), 7.17 (s, 1H), 7.10-7.00 (m, 2H), 6.95 (d, J=5.0 Hz, 1H), 5.30-5.20 (m, 1H), 4.68 (A of AB, d, J=12.0 Hz, 1H), 4.63 (B of AB, d, J=12.0 Hz, 1H), 3.57 (s, 2H), 3.51 (A of AB, d, J=11.0 Hz, 1H), 3.45 (B of AB, d, J=11.0 Hz, 1H), 3.09 (s, 3H), 3.04 (A of AB, d, J=13.6 Hz, 1H), 3.45 (B of AB, d, J=13.6 Hz, 1H), 2.94 (s, 3H), 1.58 (d, J=7.1 Hz, 3H).

Workup

  1. custompurified by flash chromatography (20 g silica, 30→80% EtOAc/hexanes) and by preparative HPLC (5% to 95% CH3CN in water containing 0.1% TFA
  2. customC18 PRO YMC 20×150 mm) to afford tert-butyl 2-({3-({[(1R)-1-(4-fluorophenyl)ethyl]amino}carbonyl)-5-[methyl(methylsulfonyl)amino]benzyl}oxy)-1-(hydroxymethyl)-1-(thien-3-ylmethyl)
  3. concentrationfollowed by concentration under a stream of nitrogen, and purification by preparative HPLC (5% to 95% CH3CN in water containing 0.1% TFA

Sources & evidence

ORD record
ord-bb1b871e9cd14b8eb2f7bef364f39fd6
Source dataset
uspto-grants-2010_11
Patent number
US07829597B2

Reaction notes

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