Methanol → 5-[5-Bromo-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]-2-thiophenecarboxylic acid

HRID 1484926Notes

Reaction equation

HRID 1484926 reaction equation
[CH3:1][OH:2].O=S(Cl)Cl.[Br:7][C:8]1[C:9]([NH:21][C:22]2[CH:26]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[NH:24][N:23]=2)=[N:10][C:11]([C:14]2[S:18][C:17](C#N)=[CH:16][CH:15]=2)=[N:12][CH:13]=1.[OH-:30].[Na+]>CO.C1COCC1>[Br:7][C:8]1[C:9]([NH:21][C:22]2[CH:26]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[NH:24][N:23]=2)=[N:10][C:11]([C:14]2[S:18][C:17]([C:1]([OH:30])=[O:2])=[CH:16][CH:15]=2)=[N:12][CH:13]=1

Participants

6

Reactant 4

HCID 887MethanolHCID 14798Sodium HydroxideHCID 24386Thionyl ChlorideHCID 58169364HCID 58169364, compound

Product 1

HCID 581692005-[5-Bromo-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]-2-thiophenecarboxylic acidYield 38.9%

Reagents, catalysts & solvents 1

HCID 21899815MeOH tetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A 100 mL round bottomed flask was charged with anhydrous methanol (50 mL). Then, SOCl2 (20 mL) was added dropwise with ice bath. After addition, the mixture was stirred for 1 h at 0° C. Then, the ice bath was removed and 5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-carbonitrile (800 mg, 2.1 mmol, 1.0 equiv.) was added. The mixture was stirred overnight at rt and the solvent was removed. Then, methanol (10 mL) and 1 N HCl aqueous (5 mL) was added. The mixture was stirred for 1 h and the solvent was removed to give a residue, which was purified by silica gel column chromatography (PE/EA/MeOH=2:1:0.06 as eluant) to give a yellow solid. This solid and NaOH (6N, 3 mL) was dissolved in methanol/THF (10 mL/10 mL). The mixture was stirred for 2 h. The solvent was removed and water (10 mL) was added. Then, 1 N HCl was added until the pH of the solution reach 2-3. The mixture was filtered and the solid was collected as acid 5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-carboxylic acid (332.5 mg, yield: 38.9%). LC-MS (m/z)=407.1 [M+H]+.

Workup

  1. additionAfter addition
  2. customThen, the ice bath was removed
  3. stirringThe mixture was stirred overnight at rt
  4. customthe solvent was removed
  5. additionThen, methanol (10 mL) and 1 N HCl aqueous (5 mL) was added
  6. stirringThe mixture was stirred for 1 h
  7. customthe solvent was removed
  8. customto give a residue, which
  9. customwas purified by silica gel column chromatography (PE/EA/MeOH=2:1:0.06 as eluant)
  10. customto give a yellow solid
  11. stirringThe mixture was stirred for 2 h
  12. customThe solvent was removed
  13. additionwater (10 mL) was added
  14. additionThen, 1 N HCl was added until the pH of the solution reach 2-3
  15. filtrationThe mixture was filtered

Sources & evidence

ORD record
ord-cb6b10f5197b4b35892a38b332f01474
Source dataset
uspto-grants-2016_08
Patent number
US09422271B2

Reaction notes

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