Ammonium Chloride → HCID 70663282, compound

HRID 878280Notes

Reaction equation

HRID 878280 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:31])[C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18](C3COC3)[CH:17]=2)=[C:4]([O:32][CH3:33])[CH:3]=1.I[CH:35]1[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]1.Cl.N[C@@H]1CCCC[C@H]1O.C[Si](C)(C)N[Si](C)(C)C.[Na].[NH4+].[Cl-]>CC(O)C.[Ni](I)I.CCOC(C)=O>[C:42]([O:41][C:39]([N:37]1[CH2:38][CH:35]([C:18]2[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=[C:16]([C:15](=[O:30])[N:14]([C:9]3[CH:10]=[N:11][CH:12]=[CH:13][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[O:32][CH3:33])[CH3:31])[CH:17]=2)[CH2:36]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]

Participants

9

Reactant 5

HCID 25517Ammonium ChlorideHCID 11000522Tert-butyl 3-iodoazetidine-1-carboxylateHCID 12228412Cyclohexanol, 2-amino-, hydrochloride (1:1), (1R,2R)-HCID 45051731Sodium hexamethyidisilazaneHCID 70663230HCID 70663230, compound

Product 1

HCID 70663282HCID 70663282, compound

Reagents, catalysts & solvents 3

HCID 26038Nickel(II) iodideCatalystHCID 3776IsopropanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

To a suspension of 3-((4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)(methyl)carbamoyl)-5-(trifluoromethyl)phenylboronic acid (0.1 g, 223 μmol, example 235, intermediate) in 2-propanol (1.0 mL) were added tert-butyl 3-iodoazetidine-1-carboxylate (63.2 mg, 223 μmol), (1R,2R)-2-aminocyclohexanol hydrochloride (2.03 mg, 13.4 μmol, CAS RN 13374-31-7), nickel(II) iodide (4.18 mg, 13.4 μmol) and sodium hexamethyldisilazan (40.9 mg, 223 μmol) and the suspension was heated in a microwave oven at 80° C. for 50 minutes. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The product (light brown solid, 0.048 g) was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless solid (0.008 g; 6%). MS (ESI): m/z=560.22 [M+H]+.

Workup

  1. customthe layers were separated
  2. extractionThe aqueous layer was extracted twice with EtOAc
  3. dry with materialThe organic layers were dried over MgSO4
  4. filtrationfiltered
  5. additiontreated with silica gel
  6. customevaporated
  7. customThe compound was purified by silica gel chromatography on a 10 g column
  8. washeluting with a gradient of n-heptane:EtOAc (100:0 to 0:100)
  9. customThe product (light brown solid, 0.048 g) was purified by preparative HPLC (Gemini NX column)

Sources & evidence

ORD record
ord-82d9aed07a314e1089191fa92f07fa47
Source dataset
uspto-grants-2015_03
Patent number
US08987307B2

Reaction notes

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