Triethylamine → 6-Methyl-pyrazine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide

HRID 218031Notes

Reaction equation

HRID 218031 reaction equation
[NH2:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([NH:12][C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)=[O:14])([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH3:21][C:22]1[N:27]=[C:26]([C:28](O)=[O:29])[CH:25]=[N:24][CH:23]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]([NH:12][C:4]12[CH2:10][CH:8]3[CH2:7][CH:6]([CH2:11][C:2]([NH:1][C:28]([C:26]4[CH:25]=[N:24][CH:23]=[C:22]([CH3:21])[N:27]=4)=[O:29])([CH2:9]3)[CH2:3]1)[CH2:5]2)=[O:14]

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 4708976-Methylpyrazine-2-carboxylic acidHCID 516892Sodium BicarbonateHCID 2724699PyBOPHCID 58358509Pyridine-2-carboxylic acid (3-amino-adamantan-1-yl)-amide2×

Product 1

HCID 446340016-Methyl-pyrazine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amideYield 74.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a round bottom flask was added pyridine-2-carboxylic acid (3-amino-adamantan-1-yl)-amide (3.10 g, 11.0 mmol, Intermediate 2), 6-methylpyrazine-2-carboxylic acid (1.83 g, 13.3 mmol; RihaChem, Kostalov, Czech Republic) and methylene chloride (120 mL). To the solution was then added PyBOP® (6.90 g, 13.3 mmol) followed by triethylamine (3.85 mL, 27.6 mmol) and the reaction was stirred for two hours at room temperature. The reaction was transferred to a 500-mL reparatory funnel with methylene chloride (50 mL) and saturated aqueous sodium bicarbonate (150 mL), and extracted with methylene chloride. The organic layer was separated and the aqueous layer was extracted again with methylene chloride (2×75 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a RP-HPLC/MS purification system (Gradient: acetonitrile in water, 27-95%, in 3.5 min with a shallow gradient from 30-60% between 0.75-3.4 min and a cycle time of 5 min. Flow rate: 100 mL/min. Mobile phase additive: 38 mM of ammonium acetate. Column: Inertsil® C8, 30×50 mm, 5 μm particle size (GL Sciences, Tokyo, Japan). Mobile phase and column temperature: 50° C.). Fractions were then concentrated under reduced pressure to remove most of the acetonitrile, the resulting aqueous layer was made basic with solid sodium carbonate (pH>10) and the aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 3.21 g (74%) of the title compound, 6-methyl-pyrazine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide, as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.17 (s, 1H), 8.58 (s, 1H), 8.54-8.50 (m, 1H), 8.17 (dt, J=7.8, 1.0 Hz, 1H), 8.06 (br s, 1H), 7.85 (td, J=7.7, 1.7 Hz, 1H), 7.77 (br s, 1H), 7.42 (ddd, J=7.6, 4.8, 1.3 Hz, 1H), 2.61-2.57 (m, 5H), 2.40-2.28 (m, 4H), 2.27-2.19 (m, 2H), 2.18-2.08 (m, 4H), 1.78-1.68 (m, 2H). ESI-MS m/z: 392.0 (M+H)+.

Workup

  1. extractionextracted with methylene chloride
  2. customThe organic layer was separated
  3. extractionthe aqueous layer was extracted again with methylene chloride (2×75 mL)
  4. washThe combined organic layers were washed with brine (150 mL)
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified on a RP-HPLC/MS purification system (Gradient
  9. waitacetonitrile in water, 27-95%, in 3.5 min with a shallow gradient from 30-60% between 0.75-3.4 min
  10. customa cycle time of 5 min
  11. custom50° C.
  12. concentrationFractions were then concentrated under reduced pressure
  13. customto remove most of the acetonitrile
  14. extractionthe aqueous layer was extracted with ethyl acetate (3×200 mL)
  15. washThe combined organic layers were washed with brine
  16. dry with materialdried over sodium sulfate
  17. filtrationfiltered
  18. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-c44ded59d03d4992aaeb8264b9cb7f52
Source dataset
uspto-grants-2012_06
Patent number
US08198275B2

Reaction notes

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