Bromide ion → HCID 131733518, compound

HRID 2283387Notes

Reaction equation

HRID 2283387 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[N:9]/[S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[C:4]([F:16])[CH:3]=1.[Br-].[Cl-].[NH4+].O.[CH2:21]1[CH2:25]OC[CH2:22]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:9][S@:10]([C:12]([CH3:13])([CH3:15])[CH3:14])=[O:11])[CH:22]2[CH2:21][CH2:25]2)=[C:4]([F:16])[CH:3]=1

Participants

6

Reactant 5

HCID 259Bromide ionHCID 962WaterHCID 8028Tetrahydrofuran2×HCID 25517Ammonium ChlorideHCID 57782005HCID 57782005, compound

Product 1

HCID 131733518HCID 131733518, compound

Procedure

Step 1 To a solution of (S)-2-methyl-propane-2-sulfinic acid 1-(4-chloro-2-fluoro-phenyl)-meth-(E)-ylideneamide (26.2 g, 0.1 mol, 1.0 eq) in anhydrous THF (700 ml) at −75° C. was added 0.5M cyclopropylmagensium bromide in THF (400 ml, 0.2 mol, 2.0 eq) dropwise at <−65° C. over 30 min. The reaction was stirred for 2 hours at <−65° C. then allowed to warm to room temperature and stirred for 4 hours. Saturated ammonium chloride solution (300 ml), was added, followed by water (150 ml). The layers were separated and the aqueous extracted with EtOAc (3×200 ml). The combined organic layers were washed with sat. brine (300 ml), dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by column chromatography on silica (500 g), eluting with 10% EtOAc/heptanesup to 80% EtOAc. (S)-2-Methyl-propane-2-sulfinic acid [(R)-(4-chloro-2-fluoro-phenyl)cyclopropyl-methyl]-amide was isolated in two batches (combined yield 26.4 g, 86.9 mmol, 87%): 1st batch; 18.4 g 1H NMR 4:1 mixture of diastereomers in favour of desired isomer, 2nd batch; 8 g 1H NMR 19:1 mixture of diastereomers in favour of desired isomer. The 2nd batch was repurified by column chromatography on silica (500 g), eluting with 10% EtOAc/heptanesup to 80% EtOAc, to give 6.6 g of pure (S)-2-methyl-propane-2-sulfinic acid [(R)-(4-chloro-2-fluoro-phenyl)-cyclopropyl-methyl]-amide. 1H NMR (270 MHz, CDCl3): 7.33 (1H, t), 7.11 (1H, dd), 7.08 (1H, dd), 3.86 (1H, dd), 3.56 (1H, d), 1.28-1.22 (1H, m), 1.18 (9H, s), 0.90-0.80 (1H, m), 0.74-0.64 (1H, m), 0.56-0.35 (2H, m).

Workup

  1. stirringstirred for 4 hours
  2. customThe layers were separated
  3. extractionthe aqueous extracted with EtOAc (3×200 ml)
  4. washThe combined organic layers were washed with sat. brine (300 ml)
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude material was purified by column chromatography on silica (500 g)
  9. washeluting with 10% EtOAc/heptanesup to 80% EtOAc

Sources & evidence

ORD record
ord-85cd8738c2194b978dc040d96f0d8ecb
Source dataset
uspto-grants-2015_09
Patent number
US09145354B2

Reaction notes

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