Ammonium Chloride → tert-butyl (3S,5S,8S)-8-(benzyloxymethyl)-6-hydroxy-3-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-2,9-dimethyldecan-5-ylcarbamate

HRID 660395Notes

Reaction equation

HRID 660395 reaction equation
[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C@H:16]([CH:29]([CH3:31])[CH3:30])[CH2:17][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=[O:20])[CH:13]=2)[CH:8]=[N:7]1.[CH2:32]([O:39][CH2:40][C@H:41]([CH:45]([CH3:47])[CH3:46])[CH2:42][Mg]Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[NH4+].[Cl-]>C1COCC1>[CH2:32]([O:39][CH2:40][C@H:41]([CH:45]([CH3:47])[CH3:46])[CH2:42][CH:19]([OH:20])[C@@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:17][C@H:16]([CH2:15][C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[N:7][N:6]2[CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:10][CH:11]=1)[CH:29]([CH3:31])[CH3:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1

Participants

5

Reactant 3

HCID 25517Ammonium ChlorideHCID 59630972tert-butyl (2S,4S)-4-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-5-methyl-1-oxohexan-2-ylcarbamateHCID 178448287HCID 178448287, compound

Product 1

HCID 59630979tert-butyl (3S,5S,8S)-8-(benzyloxymethyl)-6-hydroxy-3-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-2,9-dimethyldecan-5-ylcarbamateYield 33%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

A 250-mL, three-neck, round-bottom flask equipped with a condenser under N2 was charged with Mg powder (1.36 g, 56.7 mmol). The mixture was warmed briefly with a heat gun and a solution (S)-((2-(bromomethyl)-3-methylbutoxy)methyl)benzene (10.5 g, 37.8 mmol) in anhydrous THF (100 mL) was added dropwise. When the reaction mixture reached reflux temperature the heat gun was stopped. The mixture was stirred for an additional 30 min to afford a solution of (S)-(2-(benzyloxymethyl)-3-methylbutyl)magnesium bromide. A second 250-mL, three-neck round-bottom flask was charged with a solution of tert-butyl (2S,4S)-4-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-5-methyl-1-oxohexan-2-ylcarbamate (2.7 g, 6.3 mmol) in anhydrous THF (50 mL) and cooled to −78° C. under N2 and the solution was stirred for 30 min. The freshly prepared solution of (S)-(2-(benzyloxymethyl)-3-methylbutyl)magnesium bromide prepared above was added dropwise and the mixture was warmed to rt and stirred overnight. 10% aq NH4Cl was added and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed brine, dried and evaporated. The residue was purified by flash chromatography on silica gel to afford the crude tert-butyl (3S,5S,8S)-8-(benzyloxymethyl)-6-hydroxy-3-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-2,9-dimethyldecan-5-ylcarbamate (1.3 g, 33% yield) as an 11:5 mixture of diastereomers at the alcohol center.

Workup

  1. additionabove was added dropwise
  2. temperaturethe mixture was warmed to rt
  3. stirringstirred overnight
  4. extractionthe mixture was extracted with EtOAc (3×50 mL)
  5. washThe combined organic layers were washed brine
  6. customdried
  7. customevaporated
  8. customThe residue was purified by flash chromatography on silica gel

Sources & evidence

ORD record
ord-62c60e4cf5a341aca664d4282019e222
Source dataset
uspto-grants-2011_12
Patent number
US08084485B2

Reaction notes

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