Hydrochloric Acid → (R)-2-[(R)-2-(6-Bromo-3-fluoro-pyridin-2-yl)-2-(4-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionic acid ethyl ester

HRID 538367Notes

Reaction equation

HRID 538367 reaction equation
[CH2:1]([O:3][C:4](=[O:12])[C@:5]([OH:11])([CH3:10])[C:6]([F:9])([F:8])[F:7])[CH3:2].CC([O-])(C)C.[K+].[Br:19][C:20]1[N:25]=[C:24]([C:26]2([CH3:41])[CH2:28][N@@:27]2[S:29]([C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:23]([F:42])=[CH:22][CH:21]=1.Cl>CN(C=O)C.[Cl-].[Na+].O.CC(OC)(C)C>[CH2:1]([O:3][C:4](=[O:12])[C@:5]([O:11][CH2:41][C@@:26]([C:24]1[C:23]([F:42])=[CH:22][CH:21]=[C:20]([Br:19])[N:25]=1)([NH:27][S:29]([C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)(=[O:30])=[O:31])[CH3:28])([CH3:10])[C:6]([F:7])([F:8])[F:9])[CH3:2]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 23665647Potassium tert-butoxideHCID 26985621(R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid ethyl esterHCID 178421671HCID 178421671, compound

Product 1

HCID 86668076(R)-2-[(R)-2-(6-Bromo-3-fluoro-pyridin-2-yl)-2-(4-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionic acid ethyl esterYield 65.8%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolvent2×HCID 15413tert-Butyl methyl etherSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

A solution of (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid ethyl ester (11.93 g, 64.1 mmol) in DMF (158 ml) was evacuated/flushed with nitrogen twice. A solution of KOtBu (6.21 g, 55.5 mmol) in DMF (17 ml) was added in a dropwise while maintaining a reaction temperature of ca 25° C. using cooling with a water bath. After 15 min solid 6-bromo-3-fluoro-2-[(S)-2-methyl-1-(4-nitro-benzenesulfonyl)-aziridin-2-yl]-pyridine (17.78 g, 42.7 mmol) was added and stirring was continued for 3 h. The reaction mixture was poured onto a mixture of 1M HCl (56 ml), brine and TBME. The layers were separated, washed with brine and TBME. The combined organic layers were dried over MgSO4.H2O, filtered and evaporated. The crude reaction product was purified via chromatography on silica gel (hexanes/25-33% TBME) to yield 16.93 g of the title compound as a yellow resin that was contaminated with an isomeric side-product (ratio 70:30 by 1H-NMR).

Workup

  1. temperaturewhile maintaining a reaction temperature of ca 25° C.
  2. temperatureusing cooling with a water bath
  3. customThe layers were separated
  4. washwashed with brine and TBME
  5. dry with materialThe combined organic layers were dried over MgSO4.H2O
  6. filtrationfiltered
  7. customevaporated
  8. customThe crude reaction product
  9. customwas purified via chromatography on silica gel (hexanes/25-33% TBME)

Sources & evidence

ORD record
ord-2c6e85775ddf441abc63fbd324f2f72b
Source dataset
uspto-grants-2014_10
Patent number
US08865712B2

Reaction notes

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