Potassium Phosphate, Tribasic → tert-butyl 4-(4-(3-cyano-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazin-6-yl)phenyl)piperazine-1-carboxylate

HRID 2209228Notes

Reaction equation

HRID 2209228 reaction equation
Cl[C:2]1[N:3]=[C:4]([O:13][C@@H:14]([C@@H:16]2[CH2:20][C:19](=[O:21])[N:18]([C@@H:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH3:23])[CH2:17]2)[CH3:15])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[N:12])[CH:7]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[C:11]([C:10]1[CH:9]=[N:8][N:6]2[CH:7]=[C:2]([C:48]3[CH:47]=[CH:46][C:45]([N:42]4[CH2:41][CH2:40][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:44][CH2:43]4)=[CH:50][CH:49]=3)[N:3]=[C:4]([O:13][C@@H:14]([C@@H:16]3[CH2:20][C:19](=[O:21])[N:18]([C@@H:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[CH3:23])[CH2:17]3)[CH3:15])[C:5]=12)#[N:12]

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 52330144-(4-BOC-Piperazino)phenylboronic acidHCID 1178434716-chloro-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazine-3-carbonitrile

Product 1

HCID 117843829tert-butyl 4-(4-(3-cyano-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazin-6-yl)phenyl)piperazine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

Intermediate 5.64 (218 mg, 0.496 mmol), (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid (303 mg, 0.99 mmol), K3PO4 (420 mg, 2.0 mmol) and Bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium (II) (18 mg, 0.025 mmol) were taken up in 1,4-dioxane (7 mL) and water (0.72 mL). The stirred reaction mixture was heated to 100° C. Once complete, the reaction mixture was partitioned between EtOAc, water, and brine. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography to provide tert-butyl 4-(4-(3-cyano-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazin-6-yl)phenyl)piperazine-1-carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C37H44N7O5: 666.3; found: 666.3.

Workup

  1. customThe stirred reaction mixture
  2. customOnce complete, the reaction mixture was partitioned between EtOAc, water, and brine
  3. customThe phases were separated
  4. extractionthe aqueous phase was extracted with EtOAc
  5. dry with materialThe combined organic phase was dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude residue was purified by silica gel chromatography

Sources & evidence

ORD record
ord-9c346883d5cd4d7d9e1bc39fe83394f8
Source dataset
uspto-grants-2016_06
Patent number
US09376441B2

Reaction notes

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