Sodium borohydride → HCID 56655516, compound

HRID 1431071Notes

Reaction equation

HRID 1431071 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:44]([CH3:48])([CH3:47])[C:45]#[N:46])[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:31]=[CH:30][C:29]([C:32]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[O:33])=[CH:28][N:27]=4)[C:22](=[O:40])[N:21]([CH3:41])[N:20]=3)[C:14]=1[CH:42]=[O:43])[CH:8]=[CH:7]2.[BH4-].[Na+]>CO.ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([C:44]([CH3:48])([CH3:47])[C:45]#[N:46])[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:31]=[CH:30][C:29]([C:32]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[O:33])=[CH:28][N:27]=4)[C:22](=[O:40])[N:21]([CH3:41])[N:20]=3)[C:14]=1[CH2:42][OH:43])[CH:8]=[CH:7]2

Participants

6

Reactant 2

HCID 4311764Sodium borohydride2×HCID 87132371HCID 87132371, compound

Product 1

HCID 56655516HCID 56655516, compound

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

A solution of 2-[8-fluoro-2-(2-formyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile (224 mg, 0.35 mmol) in methanol (2.8 ml) and dichloromethane (4.3 ml) was cooled in an ice bath. To this was added a solution of sodium borohydride (65 mg, 1.7 mmol) in water (0.75 ml), via slow drop-wise addition. The mixture was stirred for 10 minutes and additional sodium borohydride (as describe above was added twice more over 20 minutes. The aqueous upper phase was carefully removed from the biphasic reaction solution. Methanol (1 ml) was added and with rapid stirring 3 more additions of aqueous sodium borohydride were made (as described above) over about 25 minutes. Water (60 ml) and dichloromethane (60 ml) were added and the material was transferred to a separatory funnel and the organic phase was collected. This was washed with an equal volume of 50% diluted brine solution and the dichloromethane phase collected. The aqueous phases were back extracted with dichloromethane (2×40 ml). The combined organic phase was dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by HPLC on silica gel, eluting with 1% to 8% methanol/dichloromethane to provide the desired product which was further purified by crystallization from hot dichloromethane/hexane to provide desired product as a white solid (120 mg). (M+H)+=650 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.81 (s, 6H) 3.53-3.81 (m, 8H) 3.83-3.91 (m, 1H) 3.92 (s, 3H) 4.26-4.45 (m, 2H) 6.62 (dd, J=7.55, 1.89 Hz, 1H) 7.00 (d, J=8.31 Hz, 1H) 7.22 (dd, J=12.46, 1.89 Hz, 1H) 7.33 (d, J=7.18 Hz, 1H) 7.42 (dd, J=7.93, 1.51 Hz, 1H) 7.53 (d, J=1.89 Hz, 1H) 7.57 (t, J=7.93 Hz, 1H) 7.65-7.70 (m, 1H) 7.78 (dd, J=8.69, 2.27 Hz, 1H) 8.41-8.47 (m, 2H) 8.70 (s, 1H).

Workup

  1. additionvia slow drop-wise addition
  2. additionabove was added twice more over 20 minutes
  3. customThe aqueous upper phase was carefully removed from the biphasic reaction solution
  4. additionMethanol (1 ml) was added
  5. stirringwith rapid stirring 3 more additions of aqueous sodium borohydride
  6. customover about 25 minutes
  7. additionWater (60 ml) and dichloromethane (60 ml) were added
  8. customthe material was transferred to a separatory funnel
  9. customthe organic phase was collected
  10. washThis was washed with an equal volume of 50% diluted brine solution
  11. customthe dichloromethane phase collected
  12. extractionThe aqueous phases were back extracted with dichloromethane (2×40 ml)
  13. dry with materialThe combined organic phase was dried with magnesium sulfate
  14. filtrationfiltered
  15. concentrationconcentrated in vacuo
  16. customThe residue was purified by HPLC on silica gel
  17. washeluting with 1% to 8% methanol/dichloromethane

Sources & evidence

ORD record
ord-1a81413627c543d598dc24816a018e89
Source dataset
uspto-grants-2015_01
Patent number
US08940741B2

Reaction notes

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