1,2-Diaminocyclohexane, trans- → Gsk-2798745

HRID 715537Notes

Reaction equation

HRID 715537 reaction equation
[CH3:1][C@:2]1([CH2:13][N:14]2[C:18]3[CH:19]=[C:20]([C:23]#[N:24])[CH:21]=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH2:12][CH2:11][CH2:10][C@:4]2([O:8][C:7](=[O:9])[NH:6][CH2:5]2)[CH2:3]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N.Br[C:42]1[N:43]=[CH:44][C:45]([C:48]([OH:51])([CH3:50])[CH3:49])=[N:46][CH:47]=1>O1CCOCC1.[Cu]I.CC#N>[OH:51][C:48]([C:45]1[N:46]=[CH:47][C:42]([N:6]2[CH2:5][C@@:4]3([CH2:10][CH2:11][CH2:12][C@@:2]([CH2:13][N:14]4[C:18]5[CH:19]=[C:20]([C:23]#[N:24])[CH:21]=[CH:22][C:17]=5[N:16]=[CH:15]4)([CH3:1])[CH2:3]3)[O:8][C:7]2=[O:9])=[N:43][CH:44]=1)([CH3:50])[CH3:49]

Participants

8

Reactant 4

HCID 438061,2-Diaminocyclohexane, trans-3×HCID 62657Potassium Phosphate, TribasicHCID 665203412-(5-Bromopyrazin-2-yl)propan-2-olHCID 712269671-(((5S,7S)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

Product 1

HCID 71227359Gsk-2798745Yield 60.6%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst3×HCID 6342AcetonitrileSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a light yellow solution of 1-(((5S,7S)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (0.050 g, 0.154 mmol) in 1,4-dioxane (2.052 mL) was added copper(I) iodide (2.94 mg, 0.015 mmol), potassium phosphate tribasic (0.065 g, 0.308 mmol), trans-1,2-diaminocyclohexane (3.71 μL, 0.031 mmol), and 2-(5-bromopyrazin-2-yl)propan-2-ol (0.040 g, 0.185 mmol). The reaction mixture was heated at 100° C. for 15 h. Then, additional copper(I) iodide (2.94 mg, 0.015 mmol) and trans-1,2-diaminocyclohexane (3.71 μL, 0.031 mmol) were added and stirred for an additional hour at 100° C. Additional copper(I) iodide (2.94 mg, 0.015 mmol) and trans-1,2-diaminocyclohexane (3.71 μL, 0.031 mmol) were then added and stirred for an additional 3 h at 100° C. The reaction was then cooled to RT and CH3CN (5 mL) was added and the mixture vacuum filtered using a Hirsch funnel. The solid was rinsed with CH3CN (3×2 mL) and the filtrate was loaded onto florisil and purified using silica gel chromatography CISCO): 0.5-2% MeOH/DCM (30 min), 12 g silica gel column. The product eluted at 19 minutes to obtain 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile as an orange foam (43 mg, 38% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.59 (s, 1H), 8.47 (s, 1H), 8.37 (s, 1H), 7.82 (d, J=8.28 Hz, 1H), 7.58 (d, J=8.28 Hz, 1H), 5.41 (s, 1H), 4.16 (br. s., 2H), 3.77-3.96 (m, 2H), 1.98 (d, J=7.03 Hz, 1H), 1.82-1.93 (m, 1H), 1.72 (d, J=14.56 Hz, 2H), 1.58-1.67 (m, 2H), 1.28-1.57 (m, 8H), 1.06 (s, 3H). MS (m/z) 461.0 (M+H+).

Workup

  1. stirringstirred for an additional 3 h at 100° C
  2. temperatureThe reaction was then cooled to RT
  3. filtrationthe mixture vacuum filtered
  4. washThe solid was rinsed with CH3CN (3×2 mL)
  5. custompurified
  6. custom0.5-2% MeOH/DCM (30 min), 12 g silica gel column
  7. washThe product eluted at 19 minutes

Sources & evidence

ORD record
ord-d864224f252c44b0a9a9d91e395094bd
Source dataset
uspto-grants-2015_11
Patent number
US09187464B2

Reaction notes

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