Diisopropylethylamine → (R)-ethyl 5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

HRID 1631307Notes

Reaction equation

HRID 1631307 reaction equation
O[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl.Cl.[F:54][C:55]1[CH:56]=[C:57]([C@H:62]2[CH2:66][CH2:65][CH2:64][NH:63]2)[C:58]([CH3:61])=[N:59][CH:60]=1>CN(C=O)C>[F:54][C:55]1[CH:56]=[C:57]([C@H:62]2[CH2:66][CH2:65][CH2:64][N:63]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[N:3]=2)[C:58]([CH3:61])=[N:59][CH:60]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 66847399(R)-5-fluoro-2-methyl-3-(pyrrolidin-2-yl)pyridine dihydrochlorideHCID 178469952HCID 178469952, compound

Product 1

HCID 86664567(R)-ethyl 5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylateYield 72.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, Step A, 372 mg, 1.8 mmol) in DMF (10 mL) was added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (874 mg, 1.98 mmol). The mixture was stirred at ambient temperature for 10 minutes then treated with DIEA (1.57 mL, 8.99 mmol) and (R)-5-fluoro-2-methyl-3-(pyrrolidin-2-yl)pyridine dihydrochloride (455 mg, 1.80 mmol). After stirring at ambient temperature for 4 hours the mixture was partitioned between 10% citric acid (50 mL) and EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic phases were washed successively with water (30 mL), saturated NaHCO3 (30 mL), water (30 mL) and brine (2×30 mL), then dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 1% MeOH/DCM to afford the product as white foam (480 mg, 72% yield). MS (apci) m/z=370.0 (M+H).

Workup

  1. stirringAfter stirring at ambient temperature for 4 hours the mixture
  2. customwas partitioned between 10% citric acid (50 mL) and EtOAc (50 mL)
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted with EtOAc (2×30 mL)
  5. washThe combined organic phases were washed successively with water (30 mL), saturated NaHCO3 (30 mL), water (30 mL) and brine (2×30 mL)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was purified by silica gel column chromatography
  10. washeluting with 1% MeOH/DCM

Sources & evidence

ORD record
ord-8a8c6ce71b9943a9bfece0e652ed67de
Source dataset
uspto-grants-2014_07
Patent number
US08791123B2

Reaction notes

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