Sodium borohydride → Pexmetinib

HRID 1666765Notes

Reaction equation

HRID 1666765 reaction equation
[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][CH2:13][C:14]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:15]=2[O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH2:26][C:27](OC)=[O:28])[N:21]=[CH:20]3)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:12][CH2:13][C:14]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:15]=2[O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH2:26][CH2:27][OH:28])[N:21]=[CH:20]3)=[O:36])[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]

Participants

4

Reactant 2

HCID 4311764Sodium borohydrideHCID 57552299Methyl 2-(5-(2-((3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)methyl)-4-fluorophenoxy)-1H-indazol-1-yl)acetate

Product 1

HCID 24765037Pexmetinib

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

A solution of methyl 2-(5-(2-((3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)methyl)-4-fluorophenoxy)-1H-indazol-1-yl)acetate (4.6 g, 7.87 mmol) in methanol (0.1M, 80 mL) was treated with sodium borohydride (893 mg, 23.6 mmol) in portions at room temperature. The mixture was stirred at room temperature for 18 hours, and the solvent evaporated in vacuo to a dark yellow residue. The residue was distributed between dichloromethane and saturated aqueous NH4Cl. The organic layer was filtered through 1PS paper, evaporated in vacuo and purified in Biotage eluting with 2-10% iPrOH/DCM. Desired fractions were evaporated in vacuo to a white foam, 2.97 g (68%). MS (APCI+) m/z 557 (M+1) was detected. 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.97 (s, 1H), 7.68 (d, 1H, J=9.1 Hz), 7.35 (s, 1H), 6.85-7.4 (m, 8H), 6.24 (s, 1H), 4.87 (t, 1H, J=5.4 Hz), 4.43 (t, 1H, J=5.6 Hz), 4.28 (d, 1H, J=5.9 Hz), 3.80 (q, 1H, J=5.5 Hz), 2.35 (s, 3H), 1.25 (s, 9H).

Workup

  1. customthe solvent evaporated in vacuo to a dark yellow residue
  2. filtrationThe organic layer was filtered through 1PS paper
  3. customevaporated in vacuo
  4. custompurified in Biotage
  5. washeluting with 2-10% iPrOH/DCM
  6. customDesired fractions were evaporated in vacuo to a white foam, 2.97 g (68%)

Sources & evidence

ORD record
ord-a8ca14699f824cf5abbed50435b28003
Source dataset
uspto-grants-2011_10
Patent number
US08044083B2

Reaction notes

Loading…