Chloroiodomethane → tert-butyl (1S)-3-chloro-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate

HRID 1869721Notes

Reaction equation

HRID 1869721 reaction equation
I[CH2:2][Cl:3].C[O:5][C:6](=O)[C@@H:7]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1.[Li+].CC([N-]C(C)C)C.C([Li])CCC>C1COCC1>[Cl:3][CH2:2][C:6](=[O:5])[C@@H:7]([NH:17][C:18](=[O:19])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1

Participants

6

Reactant 4

HCID 11644ChloroiodomethaneHCID 2724682Lithium diisopropylamideHCID 9836527(2S)-2-[(tert-Butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propionic acid methyl esterHCID 178418339Butyllithium

Product 1

HCID 9923728tert-butyl (1S)-3-chloro-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

ICH2Cl (3.54 g, 1.46 mL, 19, 0.82 mmol, 1.25 equivalent) and THF (5 mL) are added to (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid methyl ester (II, EXAMPLE 1, 5 g, 15.86 mmol, 1 equivalent). The mixture is cooled to −78° and LDA (22.3 mL, 44.60 mmol, 2.25 equivalents, 2.0 M) is added dropwise maintaining an internal temperature below −60°. Once the addition is complete, the contents are stirred for 30 min at −78° at which time n-butyllithium (15.3 mL, 19.82 mmol, 1.25 equivalents; 1.3M in hexanes) is added dropwise maintaining an internal temperature below about −60°. The reaction is stirred for 30 min then quenched into 0° hydrochloric acid (1N). Ethyl acetate is added and the phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, NMR (DMSO-d6) δ 7.47, 7.06-7.14, 4.78, 4.49, 3.20, 2.82 and 1.40; CMR (DMSO-d6) δ 200.87, 163.74, 161.20, 142.74, 112.80, 102.13, 79.04, 58.97, 47.72, 34.95 and 28.30.

Workup

  1. temperatureThe mixture is cooled to −78°
  2. temperaturemaintaining an internal temperature below −60°
  3. additionOnce the addition
  4. additionis added dropwise
  5. temperaturemaintaining an internal temperature below about −60°
  6. customthen quenched into 0° hydrochloric acid (1N)
  7. additionEthyl acetate is added
  8. customthe phases are separated
  9. extractionthe aqueous phase is extracted with ethyl acetate
  10. washThe combined organic phases are washed with saturated sodium bicarbonate
  11. dry with materialdried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-b40be63e10f241fd95e0e0c78d063252
Source dataset
uspto-grants-2009_12
Patent number
US07638646B2

Reaction notes

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