Sodium Hydroxide → 1-[3-(4-Chloro-phenyl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-piperazine

HRID 570572Notes

Reaction equation

HRID 570572 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([C:30]2C=CC=CC=2)=O)=[CH:23][CH:22]=1.[BH4-].[Na+].[OH-].[Na+]>C1COCC1.[Ti].CCOC(C)=O.O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH:28]([CH3:30])[CH2:27][C:24]4[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=4)[CH2:15][CH2:14]3)[S:10][N:9]=2)=[CH:4][CH:3]=1

Participants

10

Reactant 4

HCID 14798Sodium HydroxideHCID 2310922-(4-Methoxyphenyl)-1-phenylethan-1-oneHCID 4311764Sodium borohydrideHCID 577122563-(4-Chlorophenyl)-5-(piperazin-1-yl)-1,2,4-thiadiazole

Product 1

HCID 711864501-[3-(4-Chloro-phenyl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-piperazine

Reagents, catalysts & solvents 5

HCID 23963TitaniumCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of 3-(4-chlorophenyl)-5-(piperazin-1-yl)-1,2,4-thiadiazole (100 mg, 356 μmol), 4-methoxyphenylacetophenone (64.3 mg, 392 μmol) and titanium IV propoxide (152 mg, 158 μl, 534 μmol) in 2 mL THF was stirred for 3 h at RT. NaBH4 (40.4 mg, 1.07 mmol) was added in three portions. MeOH (0.2 mL) was added and stirred over the weekend at RT. Water (5 mL), EtOAc (10 mL) and aq. 2N NaOH (3 mL) was added, stirred for 10 min and filtered over a dicalit-plug. The aqueous layer was separated and extracted once with EtOAc (20 mL). The organic layers were washed with brine (1×20 mL), dried over Na2SO4, filtered off and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with a gradient formed from heptane and EtOAc and again with preparative HPLC to yield, after evaporation of the product containing fraction, 39 mg (25%) of the title compound as off-white solid. MS (m/e): 429.2 (MH+).

Workup

  1. stirringstirred over the weekend at RT
  2. stirringstirred for 10 min
  3. filtrationfiltered over a dicalit-plug
  4. customThe aqueous layer was separated
  5. extractionextracted once with EtOAc (20 mL)
  6. washThe organic layers were washed with brine (1×20 mL)
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered off
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified by column chromatography on silica eluting with a gradient
  11. customformed from heptane and EtOAc and again with preparative HPLC
  12. customto yield
  13. customafter evaporation of the product
  14. additioncontaining fraction, 39 mg (25%) of the title compound as off-white solid

Sources & evidence

ORD record
ord-a97133ec86884350850eda196d8f8e89
Source dataset
uspto-grants-2015_05
Patent number
US09023852B2

Reaction notes

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