4-Toluenesulfonyl chloride → (2R,5R)-5-Azidomethyl-4-[2-(6-chloro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester

HRID 1475280Notes

Reaction equation

HRID 1475280 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14]O)[N:11]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=3)[C:21]([CH3:30])([CH3:29])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N-:50]=[N+:51]=[N-:52].[Na+]>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:50]=[N+:51]=[N-:52])[N:11]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=3)[C:21]([CH3:30])([CH3:29])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 73974-Toluenesulfonyl chlorideHCID 8471TriethylamineHCID 33557Sodium AzideHCID 86723923(2R,5R)-4-[2-(6-Chloro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester

Product 1

HCID 86723926(2R,5R)-5-Azidomethyl-4-[2-(6-chloro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl esterYield 45.9%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

(2R,5R)-4-[2-(6-Chloro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (175 mg, 0.39 mmol) was dissolved in anhydrous DCM (3.87 mL) and cooled in an ice bath. Triethylamine (0.27 mL, 1.94 mmol) was added followed by toluene-4-sulfonyl chloride (148 mg, 0.77 mmol). Reaction was stirred for 1 h at 0° C. (ice bath) and gently warmed to ambient temperature over 18 h. The solvent was removed in vacuo and residue purified by column chromatography on silica gel (0-50%, EtOAc/petrol). The product (117 mg, 0.25 mmol) was dissolved in DMF (2.5 mL) and sodium azide (24 mg, 0.37 mmol) added. The reaction was heated to 65° C. for 18 h, then cooled to ambient temperature and the solvent removed in vacuo. The residue was slurried in Et2O, filtered and the filtrate evaporated in vacuo. The resulting oil was purified by column chromatography on silica gel (gradient elution, 0-75%, EtOAc/petrol), to give the title compound (81 mg, 44%) as a colourless oil. 1H NMR (Me-d3-OD): 8.14 (1H, d), 7.21 (1H, d), 7.09 (1H, dd), 4.26-4.15 (1H, m), 4.10-3.97 (3H, m), 3.76-3.46 (3H, m), 3.46-3.36 (1H, m), 3.05-2.91 (1H, m), 2.85 (1H, dd), 2.70 (1H, dd), 1.50 (9H, s), 1.38 (6H, s), 1.24 (3H, d).

Workup

  1. temperaturecooled in an ice bath
  2. customReaction
  3. temperaturegently warmed to ambient temperature over 18 h
  4. customThe solvent was removed in vacuo and residue
  5. custompurified by column chromatography on silica gel (0-50%, EtOAc/petrol)
  6. temperatureThe reaction was heated to 65° C. for 18 h
  7. temperaturecooled to ambient temperature
  8. customthe solvent removed in vacuo
  9. filtrationfiltered
  10. customthe filtrate evaporated in vacuo
  11. customThe resulting oil was purified by column chromatography on silica gel (gradient elution, 0-75%, EtOAc/petrol)

Sources & evidence

ORD record
ord-ea75fc6ba7204a24a193e5950439c012
Source dataset
uspto-grants-2015_04
Patent number
US09018214B2

Reaction notes

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