Oxalic Acid → 3-Hydroxy-2-[3-(4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate

HRID 359106Notes

Reaction equation

HRID 359106 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][N:18]1[CH:26]([OH:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].C(N(CC)CC)C.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>C1(C)C=CC=CC=1.C(Cl)Cl.C(C(C)=O)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[OH:27][CH:26]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:28])[N:18]1[CH2:17][CH2:16][CH2:15][N:11]1[CH2:10][CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1

Participants

8

Reactant 4

HCID 971Oxalic AcidHCID 8471TriethylamineHCID 1977484-(4-Fluorophenyl)-1,2,3,6-tetrahydropyridineHCID 144763692-(3-Bromopropyl)-3-hydroxy-1-isoindolinone

Product 1

HCID 200656613-Hydroxy-2-[3-(4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalateYield 59.2%

Reagents, catalysts & solvents 3

HCID 1140TolueneSolvent3×HCID 6344DichloromethaneSolventHCID 6569Methyl Ethyl KetoneSolvent2×

Procedure

A solution of 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (12.3 g) in toluene (20 cc) is added to a solution of 2-(3-bromopropyl)-3-hydroxy-1-isoindolinone (18.9 g) in toluene (200 cc), at a temperature close to 20° C. and in the course of 10 minutes, followed by a solution of triethylamine (9.8 cc) in toluene (20 cc). The mixture is agitated at a temperature close to 111° C. for 3 hours. After cooling to a temperature close to 20° C, the precipitate formed is separated by filtration and washed with toluene (3×50 cc). The organic phases are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 60° C. The residue obtained is dissolved in methylene chloride (50 cc) and the solution poured onto silica (1 kg) contained in a column of 8 cm diameter. Elution is carried out with a mixture of methylene chloride and methanol (98-2 by volume). The first 4000 cc are eliminated and the next 4000 cc are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The oil obtained is dissolved in methyl ethyl ketone (70 cc). A solution of oxalic acid (1.6 g) in methyl ethyl ketone (20 cc) is added, and agitation is maintained for about 1 hour. The precipitate formed is separated by filtration, washed with methyl ethyl ketone (20 cc), and then recrystallized from a boiling mixture of isopropanol and isopropyl ether (75-25 by volume,150 cc). 4.8 g of 3-hydroxy-2-[3-(4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate are obtained, melting at 93° C.

Workup

  1. customclose to 20° C. and in the course of 10 minutes
  2. customclose to 111° C. for 3 hours
  3. temperatureAfter cooling to a temperature
  4. customclose to 20° C
  5. customthe precipitate formed
  6. customis separated by filtration
  7. washwashed with toluene (3×50 cc)
  8. concentrationconcentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 60° C
  9. customThe residue obtained
  10. additionthe solution poured onto silica (1 kg)
  11. washElution
  12. additionis carried out with a mixture of methylene chloride and methanol (98-2 by volume)
  13. concentrationthe next 4000 cc are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C
  14. customThe oil obtained
  15. temperatureagitation is maintained for about 1 hour
  16. customThe precipitate formed
  17. customis separated by filtration
  18. washwashed with methyl ethyl ketone (20 cc)
  19. customrecrystallized from a boiling mixture of isopropanol and isopropyl ether (75-25 by volume,150 cc)

Sources & evidence

ORD record
ord-2959eaddbd594e4494772f93cdfa9468
Source dataset
uspto-grants-1991_03
Patent number
US04999355

Reaction notes

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