Sodium hydride → (R)-2-[(RS)-2-(6-Bromo-pyridin-2-yl)-2-tert-butoxycarbonylamino-propoxy]-3,3,3-trifluoro-2-methyl-propionic acid ethyl ester

HRID 538313Notes

Reaction equation

HRID 538313 reaction equation
[H-].[Na+].[C:3]([O:7][C:8]([N:10]1[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[N:17]=2)([CH3:15])[CH2:13][O:12]S1(=O)=O)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:25]([O:27][C:28](=[O:36])[C@:29](O)([CH3:34])[C:30]([F:33])([F:32])[F:31])[CH3:26]>CN(C=O)C>[CH2:25]([O:27][C:28](=[O:36])[C@:29]([O:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[N:17]=1)([NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[CH3:15])([CH3:34])[C:30]([F:32])([F:33])[F:31])[CH3:26]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 26985621(R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid ethyl esterHCID 1317311644-(6-Bromo-pyridin-2-yl)-4-methyl-2,2-dioxo-2lambda*6*-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester

Product 1

HCID 86715547(R)-2-[(RS)-2-(6-Bromo-pyridin-2-yl)-2-tert-butoxycarbonylamino-propoxy]-3,3,3-trifluoro-2-methyl-propionic acid ethyl ester

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

At 0° C., NaH (0.508 g of a 60% dispersion in mineral oil, 12.69 mmol) was added to a solution of 4-(6-bromo-pyridin-2-yl)-4-methyl-2,2-dioxo-2lambda*6*-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (3.84 g, 9.76 mmol) and (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid ethyl ester (2.54 g, 13.67 mmol) in DMF (10 ml, soln. predried over 4 Å mol. sieves). The reaction mixture was allowed to stir at rt for 30 min, then at 60° C. for 17 h. The reaction mixture was quenched with H2O and diluted with 1N aq. HCl and EtOAc. The phases were separated and the aq. phase was twice reextracted with EtOAc. The combined org. phases were washed with brines, dried over Na2SO4, filtered and concentrated. Flash chromatography on silica gel (cyclohexane: EtOAc, gradient 0-5 min 100:0, 5-30 min 90:10, 30-40 min 90:10, 40-50 min 80:20, 50-55 min 80:20) yielded the title compound (diastereomer mixture) as a clear oil. HPLC RtH4=1.39 min; ESIMS: 499, 501 [(M+H)+].

Workup

  1. waitat 60° C. for 17 h
  2. customThe reaction mixture was quenched with H2O
  3. additiondiluted with 1N aq. HCl and EtOAc
  4. customThe phases were separated
  5. washphases were washed with brines
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-18cb048f9bfd46568581f1c7ab5f97e5
Source dataset
uspto-grants-2014_10
Patent number
US08865712B2

Reaction notes

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