Methanol → Nepicastat

HRID 863073Notes

Reaction equation

HRID 863073 reaction equation
[C:1]([C:3]1[N:7]([C@H:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([F:19])=[CH:13][C:14]=3[F:18])[CH2:9]2)[C:6](=[S:20])[NH:5][CH:4]=1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].CO>C1COCC1.C(Cl)Cl.O>[NH2:2][CH2:1][C:3]1[N:7]([C@H:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([F:19])=[CH:13][C:14]=3[F:18])[CH2:9]2)[C:6](=[S:20])[NH:5][CH:4]=1

Participants

8

Reactant 4

HCID 887MethanolHCID 9855836Potassium sodium tartarate2×HCID 21226445Aluminium lithium hydrideHCID 54417352HCID 54417352, compound

Product 1

HCID 9796181NepicastatYield 58.8%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

A solution of (S)-5-cyano-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (5.0 g, 0.017 mol), prepared as in Example 19, in 75 mL of THF was stirred under argon in an ice bath and a solution of LAH in THF (1.0M, 34.3 mL, 34.3 mmol) was added dropwise over 10 minutes. The mixture was cooled to 0° C., stirred for 30 minutes, allowed to warm to room temperature, and let stand for 1.5 hours. The mixture was cooled to 0° C. and then a sufficient amount of saturated sodium potassium tartrate solution was added such that the mixture could by freely stirred. An additional 30 mL of saturated sodium potassium tartrate solution and 200 mL of 10% methanol in methylene chloride were added, the mixture was stirred for 15 minutes, and then 100-150 mL of water was added. The organic layer was separated and the aqueous phase was extracted twice with 10% methanol in methylene chloride (2×125 mL). The combined extracts were washed with 75 mL of water, dried over magnesium sulfate, and concentrated by evaporation to a residue (5.2 g). Purification by column chromatography on silica gel (elution: 5% methanol/methylene chloride) gave (S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (2.92 g, 10.0 mmol).

Workup

  1. temperatureto warm to room temperature
  2. waitlet stand for 1.5 hours
  3. temperatureThe mixture was cooled to 0° C.
  4. stirringby freely stirred
  5. stirringthe mixture was stirred for 15 minutes
  6. customThe organic layer was separated
  7. extractionthe aqueous phase was extracted twice with 10% methanol in methylene chloride (2×125 mL)
  8. washThe combined extracts were washed with 75 mL of water
  9. dry with materialdried over magnesium sulfate
  10. concentrationconcentrated by evaporation to a residue (5.2 g)
  11. customPurification by column chromatography on silica gel (elution: 5% methanol/methylene chloride)

Sources & evidence

ORD record
ord-0089f5d6086f475a97260a92fd22181f
Source dataset
uspto-grants-1998_02
Patent number
US05719280

Reaction notes

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