Diisopropylethylamine → 5-Methyl-pyrazine-2-carboxylic acid {3-[(1-methyl-1H-pyrazole-3-carbonyl)-amino]-adamantan-1-yl}-amide

HRID 218028

Reaction equation

HRID 218028 reaction equation
[C:1]12([NH2:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([NH2:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.CCN(C(C)C)C(C)C.[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[N:24]1.[CH3:31][C:32]1[N:33]=[CH:34][C:35]([C:38](O)=[O:39])=[N:36][CH:37]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([C:28]([NH:12][C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][C:3]([NH:11][C:38]([C:35]5[CH:34]=[N:33][C:32]([CH3:31])=[CH:37][N:36]=5)=[O:39])([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:30])=[N:24]1

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 1228315-Methyl-2-pyrazinecarboxylic acidHCID 213512Adamantane-1,3-diamineHCID 5731761-methyl-1H-pyrazole-3-carboxylic acidHCID 2724699PyBOP

Product 1

HCID 446332035-Methyl-pyrazine-2-carboxylic acid {3-[(1-methyl-1H-pyrazole-3-carbonyl)-amino]-adamantan-1-yl}-amideYield 38%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of adamantane-1,3-diamine (20 mg, 0.1 mmol; Zerenex Molecular Ltd., Greater Manchester, UK) in DCM (2 mL) was added DIEA (26 mg, 0.15 mmol), 1-methyl-1H-pyrazole-3-carboxylic acid (14 mg, 0.11 mmol), 5-methyl-pyrazine-2-carboxylic acid (15 mg, 0.11 mmol) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (110 mg, 0.20 mmol). After stirring for 3 hours at rt, the reaction mixture was partitioned into dichloromethane and saturated sodium bicarbonate. The organic layer was 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, 25-95%, in 3.4 minutes with a cycle time of 5 min. A shallow gradient between 25-50% of acetonitrile was used between 0.75-3.3 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 25 mM of ammonium formate. Column: Inertsil® C8, 30×50 mm, 5 μm particle size (GL Sciences, Tokyo, Japan)) to afford 15 mg (37%) of the title compound, 5-methyl-pyrazine-2-carboxylic acid {3-[(1-methyl-1H-pyrazole-3-carbonyl)-amino]-adamantan-1-yl}-amide, as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.34-8.33 (m, 1H), 7.67 (s, br, 1H), 7.33 (d, J=2.3 Hz, 1H), 6.76-6.72 (m, 2H), 3.89 (s, 3H), 2.64 (s, 3H), 2.54 (s, br, 2H), 2.37-2.09 (m, 10H), 1.73-1.68 (m, 2H). ESI-MS m/z: 395.0 (M+H)+.

Workup

  1. customthe reaction mixture was partitioned into dichloromethane and saturated sodium bicarbonate
  2. dry with materialThe organic layer was dried over sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated under reduced pressure
  5. customThe residue was purified on a RP-HPLC/MS purification system (Gradient
  6. waitacetonitrile in water, 25-95%, in 3.4 minutes with a cycle time of 5 min
  7. waitA shallow gradient between 25-50% of acetonitrile was used between 0.75-3.3 min
  8. customto separate
  9. washclose-eluting impurities

Sources & evidence

ORD record
ord-caa5feefcf7c4018b558f97c1d0f3e87
Source dataset
uspto-grants-2012_06
Patent number
US08198275B2

Linked notes

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