Sodium Bicarbonate → (S)-5-Chloro-1-(1-cyclopropyl-2-methoxyethyl)-3-(6-methoxy-2,5-dimethylpyridin-3-ylamino)pyrazin-2(1H)-one

HRID 2088509Notes

Reaction equation

HRID 2088509 reaction equation
Cl[C:2]1[C:3](=[O:16])[N:4]([C@@H:9]([CH:13]2[CH2:15][CH2:14]2)[CH2:10][O:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:17][O:18][C:19]1[N:24]=[C:23]([CH3:25])[C:22]([NH2:26])=[CH:21][C:20]=1[CH3:27].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:8][C:6]1[N:7]=[C:2]([NH:26][C:22]2[C:23]([CH3:25])=[N:24][C:19]([O:18][CH3:17])=[C:20]([CH3:27])[CH:21]=2)[C:3](=[O:16])[N:4]([C@@H:9]([CH:13]2[CH2:15][CH2:14]2)[CH2:10][O:11][CH3:12])[CH:5]=1

Participants

6

Reactant 4

HCID 516892Sodium BicarbonateHCID 2724254Sodium bis(trimethylsilyl)amideHCID 44189860(S)-3,5-Dichloro-1-(1-cyclopropyl-2-methoxyethyl)pyrazin-2(1H)-oneHCID 445964866-Methoxy-2,5-dimethylpyridin-3-amine

Product 1

HCID 44596807(S)-5-Chloro-1-(1-cyclopropyl-2-methoxyethyl)-3-(6-methoxy-2,5-dimethylpyridin-3-ylamino)pyrazin-2(1H)-oneYield 86%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (S)-3,5-dichloro-1-(1-cyclopropyl-2-methoxyethyl)pyrazin-2(1H)-one (4.00 g, 15.2 mmol) from Part G and 6-methoxy-2,5-dimethylpyridin-3-amine (2.31 g, 15.2 mmol) from Part K in THF (76 mL) at 0° C. was added NaHMDS (31.9 mL, 31.9 mmol, 1 M in THF). The reaction mixture was stirred at room temperature for 1 h. The mixture was transferred to a separatory funnel containing saturated aqueous NaHCO3 solution. The aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (10% 40% ethyl acetate in hexanes) to afford (S)-5-chloro-1-(1-cyclopropyl-2-methoxyethyl)-3-(6-methoxy-2,5-dimethylpyridin-3-ylamino)pyrazin-2(1H)-one (4.94 g, 86% yield) as a light-brown amorphous solid. Recrystallization from hexanes/ethyl acetate (1:1, 10 mL) to afforded a light-brown crystalline solid: mp 99-100.5° C.; [α]25D −52.3 (c 0.636, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.88 (s, 1H), 6.90 (s, 1H), 4.19-4.14 (m, 1H), 3.92 (s, 3H), 3.74 (dd, JAB10.3, JAX=6.2 Hz, 1H), 3.67 (dd, JBA=10.3, JBX=3.5 Hz, 1H), 3.34 (s, 3H), 2.41 (s, 3H), 2.17 (s, 3H), 1.31-1.24 (m, 1H), 0.80-0.73 (m, 1H), 0.62-0.56 (m, 1H), 0.53-0.47 (m, 1H), 0.36-0.30 (m, 1H); HRMS (ESI) m/e 379.1537 [(M+H)+, calcd for C18H24N4O3Cl 379.1537].

Workup

  1. customThe mixture was transferred to a separatory funnel
  2. extractionThe aqueous layer was extracted with EtOAc (3×100 mL)
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified by column chromatography on silica gel (10% 40% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-83af58320c6e4759b8782b51b7e27da5
Source dataset
uspto-grants-2013_05
Patent number
US08436000B2

Reaction notes

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