Tetrahydrofuran → (S)-5-bromo-1-(cyclopropyl-2-methoxyethyl)-3-[6-(difluoromethoxy)-2,5-dimethylpyridin-3-ylamino]pyrazin-2(1H)-one

HRID 386507Notes

Reaction equation

HRID 386507 reaction equation
Br[C:2]1[C:3](=[O:16])[N:4]([C@@H:9]([CH:13]2[CH2:15][CH2:14]2)COC)[CH:5]=[C:6]([Br:8])[N:7]=1.[F:17][CH:18]([F:29])[O:19][C:20]1[N:25]=[C:24]([CH3:26])[C:23]([NH2:27])=[CH:22][C:21]=1[CH3:28].[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[Na+].C1C[O:43][CH2:42]C1>>[Br:8][C:6]1[N:7]=[C:2]([NH:27][C:23]2[C:24]([CH3:26])=[N:25][C:20]([O:19][CH:18]([F:17])[F:29])=[C:21]([CH3:28])[CH:22]=2)[C:3](=[O:16])[N:4]([CH2:9][C@H:13]([CH:15]2[CH2:14][CH2:30]2)[O:43][CH3:42])[CH:5]=1

Participants

5

Reactant 4

HCID 8028TetrahydrofuranHCID 2724254Sodium bis(trimethylsilyl)amideHCID 445968056-(Difluoromethoxy)-2,5-dimethylpyridin-3-amineHCID 44596806(S)-3,5-Dibromo-1-(1-cyclopropyl-2-methoxyethyl)pyrazin-2(1H)-one

Product 1

HCID 131728799(S)-5-bromo-1-(cyclopropyl-2-methoxyethyl)-3-[6-(difluoromethoxy)-2,5-dimethylpyridin-3-ylamino]pyrazin-2(1H)-oneYield 95%

Conditions

Temperature
0 °C

Procedure

(S)-3,5-Dibromo-1-(1-cyclopropyl-2-methoxyethyl)pyrazin-2(1H)-one (18.1 g, 51.7 mmol) and 6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine (9.70 mg, 51.7 mmol) were combined in a 2 L, 3-necked round bottom flask equipped with a thermometer and an addition funnel and placed under N2. THF (360 mL) was added and the mixture was cooled to 0° C. NaHMDS (109 mL, 109 mmol, 1 M in THF) was added dropwise via the addition funnel over 15 min (the internal temperature was maintained below 5° C.). After the addition was complete, the reaction mixture was stirred at 0° C. for an additional 30 min. The reaction was quenched by the addition of saturated aqueous NH4Cl (120 mL). The mixture was transferred to a separatory funnel containing water (100 mL) and the aqueous layer was extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to afford (S)-5-bromo-1-(cyclopropyl-2-methoxyethyl)-3-[6-(difluoromethoxy)-2,5-dimethylpyridin-3-ylamino]pyrazin-2(1H)-one (22.4 g, 95% yield) as a brown solid which was used in the next step without further purification: 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.98 (s, 1H), 7.53 (s, 1H), 7.46 (t, J=73.7 Hz, 1H), 4.16-4.12 (m, 1H), 3.74 (dd, JAB=10.5, JAX=5.2 Hz, 1H), 3.66 (dd, JBA=10.3, JBX=3.3 Hz, 1H), 3.35 (s, 3H), 2.44 (s, 3H), 2.27 (s, 3H), 1.39-1.34 (m, 1H), 0.85-0.79 (m, 1H), 0.66-0.62 (m, 1H), 0.56-0.51 (m, 1H), 0.34-0.29 (m, 1H); HRMS (ESI) m/e 459.0864 [(M+H)+, calcd for C18H22N4O3BrF2 459.0843].

Workup

  1. customequipped with a thermometer and an addition funnel
  2. temperaturewas maintained below 5° C.)
  3. additionAfter the addition
  4. customThe reaction was quenched by the addition of saturated aqueous NH4Cl (120 mL)
  5. customThe mixture was transferred to a separatory funnel
  6. additioncontaining water (100 mL)
  7. extractionthe aqueous layer was extracted with ethyl acetate (3×250 mL)
  8. washThe combined organic layers were washed with brine
  9. dry with materialdried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-e6375aa5ea51496dafdd2eeb8fe31146
Source dataset
uspto-grants-2013_02
Patent number
US08372847B2

Reaction notes

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