2-Bromo-6-methylpyridine → Pyrazine-2-carboxylic acid [5-(6-methyl-pyridin-2-ylethynyl)-bicyclo[3.2.1]oct-1-yl]-amide

HRID 1503267Notes

Reaction equation

HRID 1503267 reaction equation
C1(C(O)=O)CCCC(C(O)=O)C1.[C:13]([C:15]12[CH2:22][C:19]([NH:23][C:24]([C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)=[O:25])([CH2:20][CH2:21]1)[CH2:18][CH2:17][CH2:16]2)#[CH:14].Br[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=1>C(#N)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:39][C:35]1[N:34]=[C:33]([C:14]#[C:13][C:15]23[CH2:22][C:19]([NH:23][C:24]([C:26]4[CH:31]=[N:30][CH:29]=[CH:28][N:27]=4)=[O:25])([CH2:20][CH2:21]2)[CH2:18][CH2:17][CH2:16]3)[CH:38]=[CH:37][CH:36]=1

Participants

8

Reactant 3

HCID 792052-Bromo-6-methylpyridineHCID 1072051,3-Cyclohexanedicarboxylic acidHCID 117702563N-(5-Ethynylbicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide

Product 1

HCID 71535007Pyrazine-2-carboxylic acid [5-(6-methyl-pyridin-2-ylethynyl)-bicyclo[3.2.1]oct-1-yl]-amideYield 36.1%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
70 °C

Procedure

To a stirred mixture of intermediate 1, N-(5-ethynylbicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide (40 mg, 0.16 mmol) and 2-bromo-6-methylpyridine (30 mg, 0.18 mmol) in TEA (0.5 mL) and acetonitrile (2 mL) was added Pd(PPh3)4 (2 mg, 0.02 mmol), followed by an addition of CuI (4 mg, 0.02 mmol). After heated at 70° C. for three hours, the reaction was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by Prep HPLC to afford 20 mg (36%) of the title compound, pyrazine-2-carboxylic acid [5-(6-methyl-pyridin-2-ylethynyl)-bicyclo[3.2.1]oct-1-yl]-amide, as a white solid. 1HNMR (500 MHz, CDCl3): δ 9.40 (s, 1H), 8.75 (s, 1H), 8.51 (s, 1H), 7.91 (s, 1H), 7.51 (t, J=7.5 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.06 (d, J=7.5 Hz, 1H), 2.55-2.52 (m, 4H), 2.29-1.76 (m, 11H); ESI-MS m/z: 347 (M+H)+.

Workup

  1. temperaturethe reaction was cooled to room temperature
  2. washwashed with water and brine
  3. dry with materialdried over Na2SO4
  4. concentrationconcentrated under reduced pressure
  5. customThe resulting residue was purified by Prep HPLC

Sources & evidence

ORD record
ord-f43f741af9fa46f8b553f68f6747c0a0
Source dataset
uspto-grants-2015_12
Patent number
US09212165B2

Reaction notes

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