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

HRID 1631410Notes

Reaction equation

HRID 1631410 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.[Cl:54][C:55]1[C:60]([C@H:61]2[CH2:65][CH2:64][CH2:63][NH:62]2)=[CH:59][C:58]([F:66])=[CH:57][N:56]=1>CN(C=O)C>[Cl:54][C:55]1[C:60]([C@H:61]2[CH2:65][CH2:64][CH2:63][N:62]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)=[CH:59][C:58]([F:66])=[CH:57][N:56]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 86664583(R)-2-chloro-5-fluoro-3-(pyrrolidin-2-yl)pyridine dihydrochlorideHCID 178469952HCID 178469952, compound

Product 1

HCID 86664585(R)-ethyl 5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylateYield 68%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, Step A, 275 mg, 1.33 mmol) in anhydrous DMF (5 mL) was added (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (646 mg, 1.46 mmol). The heterogeneous mixture was stirred for 10 minutes before adding DIEA (1.16 mL, 6.6 mmol), followed by addition of (R)-2-chloro-5-fluoro-3-(pyrrolidin-2-yl)pyridine dihydrochloride (363 mg, 1.33 mmol). The reaction was stirred at ambient temperature overnight to reach completion. The mixture was partitioned between 10% citric acid (30 mL) and EtOAc (30 mL), and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic phases were washed successively with water (20 mL), saturated NaHCO3 (20 mL), water (20 mL) and brine (3×20 mL), then dried (Na2SO4) and concentrated to afford the crude product as an orange foam. The crude material was purified on a 25 g Biotage SNAP silica cartridge eluting with 1% MeOH/DCM to afford the desired product as cream-colored foam (0.35 g, 68%). MS (apci pos) m/z=390.0 (M+H).

Workup

  1. stirringThe reaction was stirred at ambient temperature overnight
  2. customThe mixture was partitioned between 10% citric acid (30 mL) and EtOAc (30 mL)
  3. extractionthe aqueous layer was extracted with EtOAc (2×20 mL)
  4. washThe combined organic phases were washed successively with water (20 mL), saturated NaHCO3 (20 mL), water (20 mL) and brine (3×20 mL)
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated
  7. customto afford the crude product as an orange foam
  8. customThe crude material was purified on a 25 g Biotage SNAP silica cartridge
  9. washeluting with 1% MeOH/DCM

Sources & evidence

ORD record
ord-c8840a16a1e34abb8bf0e30af9111ced
Source dataset
uspto-grants-2014_07
Patent number
US08791123B2

Reaction notes

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