Iodoethane → 2-(4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-butyric acid methyl ester

HRID 1807241Notes

Reaction equation

HRID 1807241 reaction equation
[CH3:1][O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C@H:14]2[C@H:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[F:26])[C@:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])([C:27]#[N:28])[C@H:16]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:15]2)=[O:13])=[CH:7][CH:6]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:53](I)[CH3:54]>C1COCC1.[Cl-].[NH4+]>[CH3:1][O:2][C:3](=[O:42])[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([C@H:14]2[C@H:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[F:26])[C@:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])([C:27]#[N:28])[C@H:16]([CH2:37][C:38]([CH3:39])([CH3:41])[CH3:40])[NH:15]2)=[O:13])=[CH:9][CH:10]=1)[CH2:53][CH3:54]

Participants

6

Reactant 3

HCID 6340IodoethaneHCID 2733832Lithium HexamethyldisilazideHCID 59249533(4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-acetic acid methyl ester

Product 1

HCID 592496832-(4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-butyric acid methyl esterYield 53.9%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
-78 °C

Procedure

A mixture of chiral (4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-acetic acid methyl ester (22 mg, 0.036 mmol) was dissolved in THF (1 mL) and cooled to −78° C., then LHMDS (1 mL, 1M in THF) was added and the mixture stirred 15 min at −78° C. Ethyl iodide (0.1 mL, 0.107 mmol) was added and stirred for 1 h at −78° C., then warmed to 1 h at room temperature. The mixture was diluted with sat'd ammonium chloride solution extracted with ethyl acetate, the organic layer was separated then concentrated under reduced pressure to afford an oil that was purified by silica column chromatography (4 g Analogix column, 1-100% EtOAc/heptane) to afford 2-(4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-butyric acid methyl ester as a light yellow foam (12.4 mg, 53.9%). LCMS (ES+) m/z Calcd for C34H35Cl2F2N3O3+H [(M+H)+]: 641.20. found: 642.2.

Workup

  1. stirringstirred for 1 h at −78° C.
  2. temperaturewarmed to 1 h at room temperature
  3. extractionextracted with ethyl acetate
  4. customthe organic layer was separated
  5. concentrationthen concentrated under reduced pressure
  6. customto afford an oil that
  7. customwas purified by silica column chromatography (4 g Analogix column, 1-100% EtOAc/heptane)

Sources & evidence

ORD record
ord-31f42802f46144e5aeb13c36213bb7bd
Source dataset
uspto-grants-2013_01
Patent number
US08354444B2

Reaction notes

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