Potassium Phosphate, Tribasic → tert-Butyl 3-carbamoyl-2-(3-chloro-4-fluorophenyl)-6-cyclopropyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate

HRID 920831Notes

Reaction equation

HRID 920831 reaction equation
[C:1]([C:4]1[C:5](I)=[N:6][N:7]2[CH2:12][CH:11]([CH:13]3[CH2:15][CH2:14]3)[N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:8]=12)(=[O:3])[NH2:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[F:39]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:1]([C:4]1[C:5]([C:35]2[CH:36]=[CH:37][C:38]([F:39])=[C:33]([Cl:32])[CH:34]=2)=[N:6][N:7]2[CH2:12][CH:11]([CH:13]3[CH2:15][CH2:14]3)[N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:8]=12)(=[O:3])[NH2:2]

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 27346603-Chloro-4-fluorophenylboronic Acid (contains varying amounts of Anhydride)HCID 118071214tert-Butyl 3-carbamoyl-6-cyclopropyl-2-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate

Product 1

HCID 118071213tert-Butyl 3-carbamoyl-2-(3-chloro-4-fluorophenyl)-6-cyclopropyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylateYield 85%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

To a stirred suspension of Intermediate 348G (0.47 g, 1.087 mmol) in 1,4-dioxane (5 mL) was added K3PO4 (1.631 mL, 3.26 mmol), (3-chloro-4-fluorophenyl)boronic acid (0.246 g, 1.414 mmol) and the reaction mixture was purged with nitrogen for 10 min. PdCl2(dppf)-CH2Cl2 (0.053 g, 0.065 mmol) was then added and the reaction mixture was heated to 80° C. and stirred for 6 h. The reaction mixture was filtered through CELITE® and the filtrate was diluted with ethyl acetate (10 mL), and washed with water and brine. The organic layer was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (12 g REDISEP® column, eluting with 2% MeOH in CHCl3). Fractions containing the product were combined and evaporated to afford Intermediate 348H as an off-white solid (0.4 g, 85%). MS(ES): m/z=435 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 7.85-7.95 (m, 1H), 7.66-7.77 (m, 1H), 7.47 (t, J=9.07 Hz, 1H), 7.20-7.39 (m, 2H), 5.05 (d, J=17.37 Hz, 1H), 4.55 (d, J=17.37 Hz, 1H), 4.24 (br. s., 2H), 3.89 (br. s., 1H), 1.45 (s, 9H), 0.87-1.05 (m, 1H), 0.31-0.55 (m, 4H).

Workup

  1. customthe reaction mixture was purged with nitrogen for 10 min
  2. filtrationThe reaction mixture was filtered through CELITE®
  3. additionthe filtrate was diluted with ethyl acetate (10 mL)
  4. washwashed with water and brine
  5. dry with materialThe organic layer was dried over Na2SO4
  6. filtrationfiltered
  7. concentrationthe filtrate concentrated under reduced pressure
  8. customThe crude compound was purified by silica gel chromatography (12 g REDISEP® column, eluting with 2% MeOH in CHCl3)
  9. additionFractions containing the product
  10. customevaporated

Sources & evidence

ORD record
ord-abb463bcaa6a48fca65298a25aca102e
Source dataset
uspto-grants-2016_03
Patent number
US09273058B2

Reaction notes

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