Sodium bis(trimethylsilyl)amide → 5-chloro-1-[(2S)-2-cyclopropyl-2-methoxyethyl]-3-[[6-(difluoromethoxy)-2,5-dimethylpyridin-3-yl]amino]pyrazin-2-one

HRID 386508Notes

Reaction equation

HRID 386508 reaction equation
ClC1C(=O)N([C@@H](C2CC2)COC)C=C(Cl)N=1.[Cl:17][C:18]1[N:19]=[C:20]([NH:32][C:33]2[C:34]([CH3:44])=[N:35][C:36]([O:40][CH:41]([F:43])[F:42])=[C:37]([CH3:39])[CH:38]=2)[C:21](=[O:31])[N:22]([CH2:24][C@H:25]([CH:28]2[CH2:30][CH2:29]2)[O:26][CH3:27])[CH:23]=1.FC(F)OC1N=C(C)C(N)=CC=1C.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:17][C:18]1[N:19]=[C:20]([NH:32][C:33]2[C:34]([CH3:44])=[N:35][C:36]([O:40][CH:41]([F:43])[F:42])=[C:37]([CH3:39])[CH:38]=2)[C:21](=[O:31])[N:22]([CH2:24][C@H:25]([CH:28]2[CH2:29][CH2:30]2)[O:26][CH3:27])[CH:23]=1

Participants

5

Reactant 3

HCID 2724254Sodium bis(trimethylsilyl)amideHCID 445968056-(Difluoromethoxy)-2,5-dimethylpyridin-3-amineHCID 131730202(S)-5-Chloro-1-(cyclopropyl-2-methoxyethyl)-3-[6-(difluoromethoxy)-2,5-dimethyl-pyridin-3-ylamino]pyrazin-2(1H)-one (S)-3,5-Dichloro-1-(1-cyclopropyl-2-methoxyethyl)pyrazin-2(1H)-one

Product 1

HCID 1317288005-chloro-1-[(2S)-2-cyclopropyl-2-methoxyethyl]-3-[[6-(difluoromethoxy)-2,5-dimethylpyridin-3-yl]amino]pyrazin-2-oneYield 94%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

(S)-5-Chloro-1-(cyclopropyl-2-methoxyethyl)-3-[6-(difluoromethoxy)-2,5-dimethyl-pyridin-3-ylamino]pyrazin-2(1H)-one (S)-3,5-Dichloro-1-(1-cyclopropyl-2-methoxyethyl)pyrazin-2(1H)-one (15.0 g, 57.0 mmol) and 6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine (10.7 g, 57.0 mmol) were combined under N2 in a 2 L, 3-neck, round-bottomed flask equipped with a thermometer and an addition funnel. THF (570 mL) was added and the mixture was cooled to 0° C. NaHMDS (119.7 mL, 119.7 mmol, 1 M in THF) was added dropwise via addition funnel over 20 min at a rate to maintain the internal temperature below 5° C. After the addition was complete, the reaction mixture was stirred at 0° C. for an additional 15 min. The reaction was quenched by the addition of saturated aqueous NH4Cl (60 mL). The mixture was transferred to a separatory funnel containing water (400 mL) and the aqueous layer was extracted with ether (3×300 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The product was purified by column chromatography on silica gel (30% ethyl acetate in hexanes) to afford (S)-5-chloro-1-(cyclopropyl-2-methoxyethyl)-3-[6-(difluoromethoxy)-2,5-dimethylpyridin-3-ylamino]pyrazin-2(1H)-one (22.1 g, 94% yield) as a pale yellow solid which was subsequently recrystallized from heptane to furnish colorless needles: mp 103.4-104.4° C.; [α]25D −41.9 (c 0.807, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 8.02 (s, 1H), 7.46 (t, J=74.0 Hz, 1H), 6.96 (s, 1H), 4.19-4.14 (m, 1H), 3.75 (dd, JAB=10.3, JAX=6.3 Hz, 1H), 3.67 (dd, JBA=10.3, JBX=3.5 Hz, 1H), 3.34 (s, 3H), 2.44 (s, 3H), 2.26 (s, 3H), 1.32-1.26 (m, 1H), 0.81-0.74 (m, 1H), 0.63-0.54 (m, 1H), 0.52-0.47 (m, 1H), 0.36-0.29 (m, 1H); HRMS (ESI) m/e 415.1360 [(M+H)+, calcd for C18H22N4O3ClF2 415.1349]. Anal, Calcd for C18H21N4O3ClF2: C, 52.11; H, 5.10; N, 13.50. Found: C, 52.05; H, 4.99; N, 13.48.

Workup

  1. customequipped with a thermometer and an addition funnel
  2. temperatureto maintain the internal temperature below 5° C
  3. additionAfter the addition
  4. customThe reaction was quenched by the addition of saturated aqueous NH4Cl (60 mL)
  5. customThe mixture was transferred to a separatory funnel
  6. additioncontaining water (400 mL)
  7. extractionthe aqueous layer was extracted with ether (3×300 mL)
  8. washThe combined organic layers were washed with brine
  9. dry with materialdried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customThe product was purified by column chromatography on silica gel (30% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-3b70f304899040a390bd358685044d75
Source dataset
uspto-grants-2013_02
Patent number
US08372847B2

Reaction notes

Loading…