Triethylamine → N-((1R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}ethyl)-3,3-difluoro-1-hydroxycyclopentanecarboxamide

HRID 1160609Notes

Reaction equation

HRID 1160609 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([F:24])[C:5]([C:18]2[N:19]=[N:20][N:21]([CH3:23])[N:22]=2)=[C:6]([C:8]2[CH:9]=[C:10]([F:17])[C:11]([C@H:14]([NH2:16])[CH3:15])=[N:12][CH:13]=2)[CH:7]=1.[F:25][C:26]1([F:35])[CH2:30][CH2:29][C:28]([OH:34])([C:31](O)=[O:32])[CH2:27]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([F:24])[C:5]([C:18]2[N:19]=[N:20][N:21]([CH3:23])[N:22]=2)=[C:6]([C:8]2[CH:9]=[C:10]([F:17])[C:11]([C@H:14]([NH:16][C:31]([C:28]3([OH:34])[CH2:29][CH2:30][C:26]([F:35])([F:25])[CH2:27]3)=[O:32])[CH3:15])=[N:12][CH:13]=2)[CH:7]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 68714852((1R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}ethyl)amineHCID 68715806(+)-3,3-Difluoro-1-hydroxycyclopentanecarboxylic acid

Product 1

HCID 57608307N-((1R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}ethyl)-3,3-difluoro-1-hydroxycyclopentanecarboxamide

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of the compound of Reference Example 4 (0.766 g, 2.18 mmol), (+)-3,3-difluoro-1-hydroxycyclopentanecarboxylic acid (0.454 g, 2.73 mmol), (1H-1,2,3-benzotriazol-1-yloxy)-[tris(dimethylamino)]phosphonium hexafluorophosphate (1.35 g, 3.06 mmol) in anhydrous dichloromethane (43 mL), was added triethylamine (0.553 g, 5.46 mmol). This reaction mixture was allowed to stir at ambient temperature for 1 hour. After the reaction was judged complete by LC/MS analysis, the volume of the reaction was reduced in vacuo. The residue was taken up in EtOAc, washed with water, 0.25 N HCl and saturated aqueous sodium bicarbonate solution. The organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude residue was subjected to silica gel chromatography eluting with 0-50% EtOAc in hexanes to provide the title compound as a foam, which gave proton NMR spectra consistent with theory and a mass ion (ES+) of 499.2 for M+H+: 1H NMR (500 MHz, CDCl3) δ 8.13 (s, 1H), 7.96 (bd, NH), 7.34 (d, J=8.8 Hz, 1H), 7.26 (m, 2H), 5.41 (m, 1H), 4.342 (s, 3H), 2.82 (m, 1H), 2.46-2.25 (m, 4H), 1.92 (m, 1H), 1.45 (d, J=6.8 Hz, 3H).

Workup

  1. washwashed with water, 0.25 N HCl and saturated aqueous sodium bicarbonate solution
  2. dry with materialThe organic extracts were dried over sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated
  5. washeluting with 0-50% EtOAc in hexanes

Sources & evidence

ORD record
ord-97909c3927ef4edda60db0abb5a4e0d9
Source dataset
uspto-grants-2010_10
Patent number
US07816380B2

Reaction notes

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