Phenyl isocyanate → HCID 44629309, compound

HRID 2088511Notes

Reaction equation

HRID 2088511 reaction equation
[Cl:1][C:2]1[N:3]=[C:4]([NH:15][C:16]2[C:17]([CH3:25])=[N:18][C:19]([O:23][CH3:24])=[C:20]([CH3:22])[CH:21]=2)[C:5](=[O:14])[N:6]([CH2:8][C@H:9](C2CC2)[OH:10])[CH:7]=1.[H-].[Na+].[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[CH2:37]1[CH2:41]OC[CH2:38]1>>[C:28]1([NH:34][C:35](=[O:36])[O:10][CH2:9][C@@H:8]([N:6]2[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([NH:15][C:16]3[C:17]([CH3:25])=[N:18][C:19]([O:23][CH3:24])=[C:20]([CH3:22])[CH:21]=3)[C:5]2=[O:14])[CH:38]2[CH2:37][CH2:41]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1

Participants

5

Reactant 4

HCID 7672Phenyl isocyanateHCID 8028Tetrahydrofuran2×HCID 24758Sodium hydrideHCID 67160054HCID 67160054, compound

Product 1

HCID 44629309HCID 44629309, compoundYield 52%

Procedure

A solution of (S)-5-chloro-1-(cyclopropyl-2-hydroxyethyl)-3-(6-methoxy-2,5-dimethylpyridin-3-ylamino)pyrazin-2(1H)-one (20 mg, 0.055 mmol) from Part M in THF (1 mL) at 0° C. was treated with NaH (7 mg, 0.275 mmol, prewashed with hexanes). The cooling bath was removed and the mixture was allowed to warm to room temperature and was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C. and a solution of phenyl isocyanate (9 μL, 0.083 mmol) in 0.5 mL THF was added via cannula. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 20 min. The reaction mixture was then cooled to 0° C. and was quenched by the addition of saturated aqueous NaHCO3. The mixture was transferred to a separatory funnel containing saturated aqueous NaHCO3 (5 mL) and the aqueous layer was extracted with EtOAc (3×10 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 (20% 30% ethyl acetate in hexanes) to furnish (S)-2-(5-chloro-3-(6-methoxy-2,5-dimethylpyridin-3-ylamino)-2-oxopyrazin-1(2H)-yl)-2-cyclopropylethyl phenylcarbamate (14 mg, 52% yield) as a colorless amorphous solid: 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.92 (s, 1H), 7.30-7.26 (m, 4H), 7.06 (t, J=8.3 Hz, 1H), 6.82 (s, 1H), 6.63 (s br, 1H), 4.58 (dd, JAB=11.9, JAX=4.1 Hz, 1H), 4.48 (dd, JBA=11.9, JBX=7.6 Hz, 1H), 4.26-4.21 (m, 1H), 4.05 (s, 3H), 2.51 (s, 3H), 2.19 (s, 3H), 1.26-1.21 (m, 1H), 0.88-0.80 (m, 1H), 0.67-0.57 (m, 2H), 0.40-0.36 (m, 1H); HRMS (ESI) m/e 484.1753 [(M+H)+, calcd for C24H27N5O4Cl 484.1752].

Workup

  1. customThe cooling bath was removed
  2. temperatureThe reaction mixture was cooled to 0° C.
  3. customThe cooling bath was removed
  4. temperatureto warm to room temperature
  5. stirringwas stirred at room temperature for 20 min
  6. temperatureThe reaction mixture was then cooled to 0° C.
  7. customwas quenched by the addition of saturated aqueous NaHCO3
  8. customThe mixture was transferred to a separatory funnel
  9. additioncontaining saturated aqueous NaHCO3 (5 mL)
  10. extractionthe aqueous layer was extracted with EtOAc (3×10 mL)
  11. washThe combined organic layers were washed with brine
  12. dry with materialdried over MgSO4
  13. filtrationfiltered
  14. concentrationconcentrated
  15. customThe product was purified by column chromatography on silica gel (20% 30% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-e2554c5f64dc47b8b39b0334077033d8
Source dataset
uspto-grants-2013_05
Patent number
US08436000B2

Reaction notes

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