Methanol → N-hydroxy-4-benzyloxycarbonyl-1-{4-[5-fluoro-1-(2-trimethylsilylethane-sulfonyl)-indol-3-yl]-piperidine-1-sulfonyl}piperazine-2-(RS)-carboxamide

HRID 843006Notes

Reaction equation

HRID 843006 reaction equation
[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([F:35])[CH:33]=4)[N:28]([S:36]([CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])(=[O:38])=[O:37])[CH:27]=3)[CH2:22][CH2:21]2)(=[O:19])=[O:18])[CH:13]([C:45](O)=[O:46])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:56][O:57][Si](C)(C)C.CO>C(Cl)Cl.CN(C=O)C>[OH:57][NH:56][C:45]([CH:13]1[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:16][CH2:15][N:14]1[S:17]([N:20]1[CH2:21][CH2:22][CH:23]([C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([F:35])[CH:33]=3)[N:28]([S:36]([CH2:39][CH2:40][Si:41]([CH3:43])([CH3:44])[CH3:42])(=[O:37])=[O:38])[CH:27]=2)[CH2:24][CH2:25]1)(=[O:18])=[O:19])=[O:46]

Participants

7

Reactant 4

HCID 887MethanolHCID 65578Oxalyl chlorideHCID 898151,1,1-trimethyl-N-((trimethylsilyl)oxy)silylamineHCID 15486972HCID 15486972, compound

Product 1

HCID 15486973N-hydroxy-4-benzyloxycarbonyl-1-{4-[5-fluoro-1-(2-trimethylsilylethane-sulfonyl)-indol-3-yl]-piperidine-1-sulfonyl}piperazine-2-(RS)-carboxamideYield 86.3%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent

Procedure

To a solution of 4-benzyloxycarbonyl-1-{4-[5-fluoro-1-(2-trimethylsilylethane-sulfonyl)indol-3-yl]piperidine-1-sulfonyl}piperazine-2-(RS)-carboxylic acid(288 mg, 0.40 mmol), [prepared as described in Step 6 above] in methylene chloride (5 ml) at 0° C. were added a few drops of DMF and oxalyl chloride (89 ml, 1.0 mmol). The reaction mixture was warmed to RT over 1 h, and stirring was continued for an additional 14 h. The reaction mixture was concentrated in vacuo, redissolved in methylene chloride (5 ml) and cooled to 0° C. N,O-bis-trimethylsilyl hydroxylamine (0.304 ml, 1.42 mmol) added, the reaction was warmed to RT, stirred for 3 h, and then recooled to 0° C. After adding methanol (3 ml), the mixture was stirred for an additional 30 min., and then concentrated in vacuo. The residue was partitioned between methylene chloride (50 ml) and aqueous 2.4 M HCl (10 ml), the organic layer was separated and washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and concentrated in vacuo to afford N-hydroxy-4-benzyloxycarbonyl-1-{4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)-indol-3-yl]-piperidine-1-sulfonyl}piperazine-2-(RS)-carboxamide as a yellow foam (250 mg, 86%). The residue was used without further purification.

Workup

  1. concentrationThe reaction mixture was concentrated in vacuo
  2. dissolutionredissolved in methylene chloride (5 ml)
  3. temperaturecooled to 0° C
  4. temperaturethe reaction was warmed to RT
  5. stirringstirred for 3 h
  6. customrecooled to 0° C
  7. stirringthe mixture was stirred for an additional 30 min.
  8. concentrationconcentrated in vacuo
  9. customThe residue was partitioned between methylene chloride (50 ml) and aqueous 2.4 M HCl (10 ml)
  10. customthe organic layer was separated
  11. washwashed with saturated aqueous sodium bicarbonate
  12. dry with materialdried over MgSO4
  13. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-966a878e995e47e38334966d1b242a90
Source dataset
uspto-grants-2002_04
Patent number
US06376506B1

Reaction notes

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