Acetic Acid → Pomalidomide

HRID 1671573Notes

Reaction equation

HRID 1671573 reaction equation
Cl.[NH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=O)[C:4]=1[C:12]([OH:14])=O.Cl.N[CH:17]1[CH2:23][C:22](=[O:24])[NH:21][C:19](=[O:20])[CH2:18]1.C(O)(=O)C.C([N:31](CC)CC)C.NC1C=CC=C(C(O)=O)C=1C(O)=O>O.C(#N)C>[NH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]2[C:4]=1[C:12](=[O:14])[N:31]([CH:23]1[CH2:17][CH2:18][C:19](=[O:20])[NH:21][C:22]1=[O:24])[C:6]2=[O:8]

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 8471TriethylamineHCID 794903-Aminophthalic acidHCID 813751,2-Benzenedicarboxylic acid, 3-amino-, hydrochloride (1:1)HCID 673455864-Aminopiperidine-2,6-dione hydrochloride

Product 1

HCID 134780Pomalidomide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
22.5 °C

Procedure

A mixture of 3-aminophthalic acid hydrochloride (200 g, 0.92 mol, from Prosynth Ltd., Suffolk, UK), 3-aminoglutarimide hydrochloride (159 g, 0.96 mol, from Evotec OAI, Hamburg, Germany), acetonitrile (2.0 L), and acetic acid (577 g, 9.6 mol, from Fisher Scientifc) was charged into a reaction vessel. After the mixture was stirred for 15 minutes, triethylamine (465.0 g, 4.6 mol, from Aldrich, Milwaukee, Wis.) was added dropwise over 30-35 minutes while the reaction temperature was maintained at 20-25° C. Next, the reaction mixture was stirred further for 10-15 minutes and then refluxed at about 85 to 87° C. for about 5 to 7 hours or until the in-process control, i.e., HPLC AP at 240 nm, indicates that <2% of the 3-aminophthalic acid remained in the reaction mixture. After the reaction mixture was cooled to about 20 to 25° C. over 1-2 hours, 1.0 L of water was charged over 15-30 minutes at about 20 to 25° C. The resulting mixture was stirred at about 15 to 20° C. for about 20 to 30 minutes to provide a yellow solid precipitate, which was filtered, washed with DI water (3×1.0 L) and acetonitrile (2×500 mL), and then dried at about 35 to 40° C in vacuo to a constant weight at 210.0 g (84 %).

Workup

  1. additionwas charged into a reaction vessel
  2. stirringNext, the reaction mixture was stirred further for 10-15 minutes
  3. temperaturerefluxed at about 85 to 87° C. for about 5 to 7 hours
  4. temperatureAfter the reaction mixture was cooled to about 20 to 25° C. over 1-2 hours
  5. stirringThe resulting mixture was stirred at about 15 to 20° C. for about 20 to 30 minutes
  6. customto provide a yellow solid precipitate, which
  7. filtrationwas filtered
  8. washwashed with DI water (3×1.0 L) and acetonitrile (2×500 mL)
  9. customdried at about 35 to 40° C in vacuo to a constant weight at 210.0 g (84 %)

Sources & evidence

ORD record
ord-8d52577e50434ed5997bdf6518666a0c
Source dataset
uspto-grants-2011_08
Patent number
US07994327B2

Reaction notes

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