tert-Butanol → (R)-2,3,5,6-tetrafluoro-4-(4-((3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)methyl)-1H-1,2,3-triazol-1-yl)benzoic acid

HRID 238832Notes

Reaction equation

HRID 238832 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][C:31]([NH:33][CH2:34][C:35]#[CH:36])=[O:32])([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.C(O)(C)(C)C.[N:42]([C:45]1[C:53]([F:54])=[C:52]([F:55])[C:48]([C:49]([OH:51])=[O:50])=[C:47]([F:56])[C:46]=1[F:57])=[N+:43]=[N-:44].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>O>[F:55][C:52]1[C:53]([F:54])=[C:45]([N:42]2[CH:36]=[C:35]([CH2:34][NH:33][C:31]([NH:30][C@@:15]([C:4]3[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=[C:2]([F:1])[CH:3]=3)([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:32])[N:44]=[N:43]2)[C:46]([F:57])=[C:47]([F:56])[C:48]=1[C:49]([OH:51])=[O:50]

Participants

6

Reactant 4

HCID 6386tert-ButanolHCID 27625784-Azidotetrafluorobenzoic acidHCID 23667548Sodium AscorbateHCID 59458731(R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(prop-2-ynyl)urea

Product 1

HCID 59458636(R)-2,3,5,6-tetrafluoro-4-(4-((3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)methyl)-1H-1,2,3-triazol-1-yl)benzoic acidYield 78%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent2×

Procedure

To a suspension of (R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(prop-2-ynyl)urea (5.0 mg, 0.01 mmol), prepared as described in Procedure 3, 4, 5, 6 and 12, in a 1:1 mixture of water and tert-butyl alcohol (100 μL) was added 4-azido-2,3,5,6-tetrafluorobenzoic acid (2.3 mg, 0.01 mmol), followed by sodium ascorbate (1 M solution in H2O, 100 μL) and CuSO4.5H2O (1 mg). The reaction mixture was stirred vigorously overnight in a sealed vial. The reaction mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic portions were concentrated and the residue was dissolved in MeOH and purified by preparative HPLC (Phenoma Onyx Monolithic 10×100 mm; eluting with 10%-90% MeCN/H2O with 0.1% TFA, monitoring at 220 nm) to provide (R)-2,3,5,6-tetrafluoro-4-(4-((3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)methyl)-1H-1,2,3-triazol-1-yl)benzoic acid (Example 319, 5.7 mg, 78% yield). LC/MS: RT=3.610 min [M+H] 742.3 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm). 1H NMR (500 MHz, MeOH-d4) δ 8.02 (s, 1H), 7.10-6.79 (m, 11H), 6.53 (d, J=5 Hz, 2H), 6.27-6.04 (m, 1H), 4.38-4.31 (m, 2H), 3.81 (d, J=15 Hz, 1H), 3.73 (d, J=10 Hz, 1H).

Workup

  1. customprepared
  2. extractionextracted with EtOAc (3×)
  3. concentrationThe combined organic portions were concentrated
  4. dissolutionthe residue was dissolved in MeOH
  5. custompurified by preparative HPLC (Phenoma Onyx Monolithic 10×100 mm; eluting with 10%-90% MeCN/H2O with 0.1% TFA, monitoring at 220 nm)

Sources & evidence

ORD record
ord-a3217b289c564a0e88dfc7ce5d1910ce
Source dataset
uspto-grants-2014_02
Patent number
US08642576B2

Reaction notes

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