Sodium hydride → HCID 58920257, compound

HRID 1365532Notes

Reaction equation

HRID 1365532 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31]([NH:33][CH2:34][C:35]([F:39])([F:38])[CH2:36][OH:37])=[O:32])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31](=[O:32])[NH:33][CH2:34][C:35]([F:38])([F:39])[CH2:36][O:37][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:27])([F:28])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 79177tert-Butyl bromoacetateHCID 58919972HCID 58919972, compound

Product 1

HCID 58920257HCID 58920257, compoundYield 43%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

(S)-1-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(2,2-difluoro-3-hydroxypropyl)urea (12 mg, 0.027 mmol), prepared as described in Procedures 3, 5, 6, 7 and 8, in THF (0.5 mL) was added NaH (4 mg, 60% in mineral oil, 0.1 mmol). After 2 min, tert-butyl 2-bromoacetate (6 mg, 0.04 mmol) was added. The reaction mixture was stirred for 15 min, filtered and concentrated in vacuo. The residue was purified by preparative HPLC Shimadzu-Phenomenex Luna C18 column, 21.2×100 mm eluting with 10-90% CH3CN (90% in H2O, 0.1% TFA) gradient over 15 min with flow rate 20 mL/min and UV detection at 220 nm to give (S)-tert-butyl 2-(3-(3-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)ureido)-2,2-difluoropropoxy)acetate as a white solid (8 mg, 43% yield). LCMS RT=4.12 min, [M+H] 694.35 (LCMS Method 1) NMR: 500 MHz 1H (CDCl3) 8.25 ppm, 1H, m; 7.67 ppm, 1H, m; 7.50 ppm, 1H, m; 7.17 ppm, 1H, d; 7.06 ppm, 6H, m; 6.89 ppm, 1H, m; 6.61 ppm, 2H, m; 5.87 ppm, 1H, t; 4.35 ppm, 1H, d; 4.07 ppm, 1H, d; 3.95 ppm, 1H, d; 3.88 ppm, 1H, m; 3.74 ppm, 2H, m; 3.55 ppm, 2H, m; 1.42 ppm, 9H, m.

Workup

  1. filtrationfiltered
  2. concentrationconcentrated in vacuo
  3. customThe residue was purified by preparative HPLC Shimadzu-Phenomenex Luna C18 column, 21.2×100 mm
  4. washeluting with 10-90% CH3CN (90% in H2O, 0.1% TFA) gradient over 15 min with flow rate 20 mL/min and UV detection at 220 nm

Sources & evidence

ORD record
ord-85af8fc4db624388aa7785111fcfd24a
Source dataset
uspto-grants-2011_02
Patent number
US07888376B2

Reaction notes

Loading…