Dichloromethane → 2-(8-Fluoro-2-{3-hydroxymethyl-4-[1-methyl-5-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-pyridin-2-yl}-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-proprionitrile

HRID 337325Notes

Reaction equation

HRID 337325 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:40]([CH3:44])([CH3:43])[C:41]#[N:42])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[C:18]([CH:19]=[O:20])=[C:17]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[CH:37]=[C:31]5[CH2:32][N:33]([CH3:36])[CH2:34][CH2:35][N:30]5[N:29]=4)[C:24](=[O:38])[N:23]([CH3:39])[N:22]=3)[CH:16]=[CH:15][N:14]=1)[CH:8]=[CH:7]2.C(Cl)Cl.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:40]([CH3:44])([CH3:43])[C:41]#[N:42])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[C:18]([CH2:19][OH:20])=[C:17]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[CH:37]=[C:31]5[CH2:32][N:33]([CH3:36])[CH2:34][CH2:35][N:30]5[N:29]=4)[C:24](=[O:38])[N:23]([CH3:39])[N:22]=3)[CH:16]=[CH:15][N:14]=1)[CH:8]=[CH:7]2

Participants

5

Reactant 3

HCID 6344DichloromethaneHCID 4311764Sodium borohydrideHCID 866769392-(8-Fluoro-2-{3-formyl-4-[1-methyl-5-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-pyridin-2-yl}-1-oxo-1,2dihydro-isoquinolin-6-yl)-2-methyl-propionitrile

Product 1

HCID 712577582-(8-Fluoro-2-{3-hydroxymethyl-4-[1-methyl-5-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-pyridin-2-yl}-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-proprionitrile

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
0 °C

Procedure

In a 25 mL round-bottomed flask, 2-(8-fluoro-2-{3-formyl-4-[1-methyl-5-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-pyridin-2-yl}-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl -propionitrile (800 mg, 1.35 mmol, 1.0 equiv.) was combined with dry DCM (25 ml) and dry methanol (5 mL) to give a light yellow solution. The reaction mixture was cooled to 0° C. and sodium borohydride (91.8 mg, 2.43 mmol, Eq: 1.8) was added. The reaction mixture was stirred at 0° C. for 40 min. and then was quenched with 2 mL saturated NH4Cl with stirring for 5 min. The reaction mixture was poured into 100 mL H2O and extracted with DCM (3×150 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude foam was taken up in 20 mL DCM and 15 mL methanol. To this mixture was added 200 mg of 10% Pd/C (Degussa brand). The reaction mixture was stirred at room temperature for 2 h. The solid was removed by filtration and washed several times with 10% methanol in DCM. The combined filtrate and washes were concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 4% MeOH holding gradient as each peak came off). Center cut fractions were concentrated to give a glass, which was triturated with ether to afford 2-(8-fluoro-2-{3-hydroxymethyl-4-[1-methyl-5-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-pyridin-2-yl}-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-proprionitrile as an off-white solid. (M+H)+=596 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.81 (s, 6 H) 2.52 (s, 3 H) 2.94 (t, J=5.67 Hz, 2 H) 3.65 (d, J=2.27 Hz, 2 H) 3.90 (s, 3 H) 4.05-4.22 (m, 3 H) 4.42-4.60 (m, 2 H) 5.85 (s, 1 H) 6.66 (dd, J=7.55, 1.89 Hz, 1 H) 7.22 (dd, J=12.46, 1.89 Hz, 1 H) 7.35 (d, J=7.55 Hz, 1 H) 7.53 (d, J=1.89 Hz, 1 H) 7.62 (d, J=4.91 Hz, 1 H) 7.92 (s, 1 H) 7.99 (s, 1 H) 8.68 (d, J=4.91 Hz, 1 H).

Workup

  1. customto give a light yellow solution
  2. customwas quenched with 2 mL saturated NH4Cl
  3. stirringwith stirring for 5 min
  4. additionThe reaction mixture was poured into 100 mL H2O
  5. extractionextracted with DCM (3×150 mL)
  6. dry with materialThe combined organic layers were dried over Na2SO4
  7. concentrationconcentrated in vacuo
  8. additionTo this mixture was added 200 mg of 10% Pd/C (Degussa brand)
  9. stirringThe reaction mixture was stirred at room temperature for 2 h
  10. customThe solid was removed by filtration
  11. washwashed several times with 10% methanol in DCM
  12. concentrationThe combined filtrate and washes were concentrated in vacuo
  13. customThe crude material was purified by flash chromatography (silica gel, 40 g, 0% to 4% MeOH holding gradient as each peak
  14. concentrationwere concentrated
  15. customto give a glass, which
  16. customwas triturated with ether

Sources & evidence

ORD record
ord-334bb1df1cf54df7ab9c1b09be9deabd
Source dataset
uspto-grants-2014_11
Patent number
US08889682B2

Reaction notes

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