Sodium Iodide → 9-(4-(2,2-difluoroethoxy)phenyl)-N-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-fluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine 2,2,2-trifluoroacetate

HRID 1803289Notes

Reaction equation

HRID 1803289 reaction equation
Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[NH:22][N:21]=[C:20]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[C:34]([CH3:35])=[N:33][C:32]([CH3:36])=[N:31]3)=[C:26]([F:37])[CH:25]=2)[N:19]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([F:17])[F:16])=[CH:9][CH:8]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50]>CC(C)=O>[F:52][C:51]([F:54])([F:53])[C:49]([OH:55])=[O:50].[F:16][CH:15]([F:17])[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:22]3[N:21]=[C:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([N:30]5[C:34]([CH3:35])=[N:33][C:32]([CH3:36])=[N:31]5)=[C:26]([F:37])[CH:25]=4)[N:19]=[C:18]23)=[CH:12][CH:11]=1

Participants

6

Reactant 4

HCID 5238Sodium IodideHCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 866499325-(5-chloro-1-(4-(2,2-difluoroethoxy)phenyl)pentyl)-N-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-fluorophenyl)-1H-1,2,4-triazol-3-amine

Product 1

HCID 866499339-(4-(2,2-difluoroethoxy)phenyl)-N-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-fluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine 2,2,2-trifluoroacetateYield 16%

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent

Procedure

A solution of 5-(5-chloro-1-(4-(2,2-difluoroethoxy)phenyl)pentyl)-N-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-fluorophenyl)-1H-1,2,4-triazol-3-amine (787 mg, 1.47 mmol), sodium iodide (1.10 g, 7.37 mmol), and diisopropylethylamine (1.29 mL, 7.37 mmol) in acetone (30 mL) was heated in a sealed vessel at 100° C. for 3 h. The reaction was concentrated in vacuo. After an aqueous workup, the crude organic concentrate was purified using reverse phase preparatory HPLC (MeOH/water/TFA) to afford 145 mg (16% yield) of the titled compound as the TFA salt. LC-MS (M+H)+ 498.3. 1H NMR (500 MHz, CHLOROFORM-d) d ppm 9.45 (1 H, br. s.), 7.69 (1 H, dd, J=12.5, 2.1 Hz), 7.29 (1H, t, J=8.5 Hz), 7.18 (1 H, d, J=8.5 Hz), 7.04 (2 H, d, J=8.5 Hz), 6.93 (2 H, d, J=8.5 Hz), 6.08 (1 H, tt, J=55.1, 4.1 Hz), 4.40 (1 H, d, J=7.9 Hz), 4.30-4.37 (1 H, m), 4.21-4.30 (1 H, m), 4.17 (2 H, td, J=13.0, 4.1 Hz), 2.45 (3H, s), 2.42 (3 H, s), 2.25-2.35 (1 H, m), 2.06-2.17 (1 H, m), 1.84-2.04 (4 H, m).

Workup

  1. concentrationThe reaction was concentrated in vacuo
  2. concentrationAfter an aqueous workup, the crude organic concentrate
  3. customwas purified

Sources & evidence

ORD record
ord-e006f35e1b38440590f04912f5cfb870
Source dataset
uspto-grants-2013_01
Patent number
US08349880B2

Reaction notes

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