Methanol → HCID 66743241, compound

HRID 1431212Notes

Reaction equation

HRID 1431212 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:43]([CH3:47])([CH3:46])[C:44]#[N:45])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[C:23]([NH:25][C:26]4[CH:38]=[C:29]5[CH2:30][N:31]([CH:34]6[CH2:37][O:36][CH2:35]6)[CH2:32][CH2:33][N:28]5[N:27]=4)[C:22](=[O:39])[N:21]([CH3:40])[N:20]=3)[C:14]=1[CH:41]=[O:42])[CH:8]=[CH:7]2.CO.[BH4-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:43]([CH3:47])([CH3:46])[C:44]#[N:45])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[C:23]([NH:25][C:26]4[CH:38]=[C:29]5[CH2:30][N:31]([CH:34]6[CH2:35][O:36][CH2:37]6)[CH2:32][CH2:33][N:28]5[N:27]=4)[C:22](=[O:39])[N:21]([CH3:40])[N:20]=3)[C:14]=1[CH2:41][OH:42])[CH:8]=[CH:7]2

Participants

5

Reactant 3

HCID 887MethanolHCID 4311764Sodium borohydrideHCID 86662324HCID 86662324, compound

Product 1

HCID 66743241HCID 66743241, compoundYield 19.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

6-chloro-2-methyl-4-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-pyridazin-3(2H)-one (prepared as described in example 60, 65 mg, 194 μmol) bis(pinacolato)diboron (54.1 mg, 213 μmol) and potassium acetate (57.0 mg, 581 μmol) were suspended in dioxane (9 ml). The reaction mixture was degassed under argon. X-PHOS (13.8 mg, 29.0 μmol) and palladium(II) acetate (2.17 mg, 9.68 μmol) were added and the reaction mixture was stirred at 100° C. (external temperature) for 45 min under an argon atmosphere. LCMS (taken in methanol) showed some conversion to boronic acid (M+1=347) and some of the undesired 2-methyl-4-(5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-2H-pyridazin-3-one. Heating was turned down to 80° C. The flask was raised out of the heating bath, but continued stirring. 2-(2-(3-bromo-2-formylphenyl)-8-fluoro-1-oxo-1,2-dihydroisoquinolin-6-yl)-2-methylpropanenitrile (prepared as describe in example 15, 80 mg, 194 μmol) in 2 mL dioxanes and potassium carbonate (80.3 mg, 581 μmol) were added, followed by 1 mL H2O. Tricyclohexylphosphine (5.43 mg, 19.4 μmol) and bis(dibenzylideneacetone)-palladium (0) (5.57 mg, 9.68 μmol) were added. The reaction mixture was heated with vigorous stirring at 80° C. for 1.5 h. The crude reaction was poured onto H2O and EtOAc and extracted 3 times with EtOAc and 1 time with DCM. The combined organic extracts were washed with brine and dried over MgSO4. The crude material was purified by flash chromatography (silica gel, 24 g, 1% to 5% MeOH in DCM) to afford approx. 90 mg the intermediate 2-(8-fluoro-2-(2-formyl-3-(1-methyl-5-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-2-methylpropanenitrile. In a 25 mL round-bottomed flask, 2-(8-fluoro-2-(2-formyl-3-(1-methyl-5-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-2-methylpropanenitrile (90 mg, 142 μmol) was combined with dry CH2Cl2 (2 ml) and dry MeOH (0.5 mL) to give a light yellow solution. The solution was cooled to 0° C. Sodium borohydride (9.66 mg, 255 μmol) was added. The reaction mixture was stirred at 0° C. for 40 min. Complete by LCMS. Quenched with sat'd NH4Cl. The reaction mixture was poured into 25 mL H2O and extracted with DCM (2×50 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 0% to 3% MeOH). Pure fractions were concentrated to give a glass, which was dissolved in 1 mL DCM and precipitated with 20 mL ether to afford the desired product (18 mg) as a white solid. (M+H)+=637 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.81 (s, 6H) 2.90 (t, J=5.48 Hz, 2H) 3.55-3.71 (m, 2H) 3.77-3.86 (m, 1H) 3.89 (s, 3H) 4.17 (t, J=5.48 Hz, 2H) 4.26-4.42 (m, 2H) 4.66-4.87 (m, 4H) 5.83 (s, 1H) 6.62 (dd, J=7.55, 1.89 Hz, 1H) 7.22 (dd, J=12.28, 1.70 Hz, 1H) 7.34 (d, J=7.18 Hz, 1H) 7.41 (dd, J=7.74, 1.32 Hz, 1H) 7.50-7.61 (m, 2H) 7.63-7.72 (m, 1H) 7.85 (s, 1H) 7.95 (s, 1H).

Workup

  1. customto give a light yellow solution
  2. customQuenched with sat'd NH4Cl
  3. additionThe reaction mixture was poured into 25 mL H2O
  4. extractionextracted with DCM (2×50 mL)
  5. dry with materialThe organic layers were dried over Na2SO4
  6. concentrationconcentrated in vacuo
  7. customThe crude material was purified by flash chromatography (silica gel, 24 g, 0% to 3% MeOH)
  8. concentrationPure fractions were concentrated
  9. customto give a glass, which
  10. customprecipitated with 20 mL ether

Sources & evidence

ORD record
ord-7cd9808e2f384bde80c8c9992cc1bc50
Source dataset
uspto-grants-2015_01
Patent number
US08940741B2

Reaction notes

Loading…