Succinic Acid → 1-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-pyrrolidine-2,5-dione hydrochloride

HRID 251867Notes

Reaction equation

HRID 251867 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][C@H:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20].[C:21](O)(=[O:27])[CH2:22][CH2:23][C:24](O)=[O:25].C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][C@H:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:27]

Participants

4

Reactant 3

HCID 1110Succinic Acid2×HCID 11430Potassium CarbonateHCID 66864574(R)-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine

Product 1

HCID 668653571-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-pyrrolidine-2,5-dione hydrochloride

Conditions

Temperature
135 °C

Procedure

(R)-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (100 mg; enantiomer B, preparation as described in WO2004085404) was initially charged in a flask together with succinic acid (58 mg). To this was added polyphosphoric acid (approx. 2 ml). The reaction mixture was subsequently stirred at 135° C. After 4 hours, a little more succinic acid (˜9 mg) was added. After a further 2 h at 135° C., the mixture was left to stand at room temperature overnight. For workup, the mixture was poured onto ice-water, and the acidic phase was adjusted to pH 10 with saturated potassium carbonate solution and then extracted three times with ethyl acetate. The combined organic phases were washed once with water, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by means of preparative HPLC. The fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with potassium carbonate and extracted three times with ethyl acetate. It was dried over magnesium sulfate, then filtered and concentrated to dryness. The residue was taken up with aqueous hydrochloric acid and freeze-dried.

Workup

  1. waitAfter a further 2 h at 135° C.
  2. waitthe mixture was left
  3. waitto stand at room temperature overnight
  4. additionFor workup, the mixture was poured onto ice-water
  5. extractionextracted three times with ethyl acetate
  6. washThe combined organic phases were washed once with water
  7. dry with materialdried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe crude product was purified by means of preparative HPLC
  11. customthe acetonitrile was removed on a rotary evaporator
  12. extractionextracted three times with ethyl acetate
  13. dry with materialIt was dried over magnesium sulfate
  14. filtrationfiltered
  15. concentrationconcentrated to dryness
  16. customfreeze-dried

Sources & evidence

ORD record
ord-3b592f5ee3ce438fa8e30b05d71910e4
Source dataset
uspto-grants-2011_01
Patent number
US07868003B2

Reaction notes

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