Sodium borohydride → Pexmetinib

HRID 1665999Notes

Reaction equation

HRID 1665999 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-f424b207785c47a396a2114472974a11
Source dataset
uspto-grants-2011_10
Patent number
US08039639B2

Reaction notes

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