Triethylamine → (3S)-tert-butyl 3-(acetylthiomethyl)-4-(2-(3-cyano-4-fluoro-2-methylphenyl)-2-hydroxyethyl)piperazine-1-carboxylate

HRID 1502005Notes

Reaction equation

HRID 1502005 reaction equation
[C:1]([C:3]1[C:4]([CH3:28])=[C:5]([CH:10]([OH:27])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]2[CH2:25]O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C(N(CC)CC)C.S(Cl)(C)(=O)=O.[C:41]([O-:44])(=[S:43])[CH3:42].[K+]>C1COCC1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[C:41]([S:43][CH2:25][C@H:13]1[N:12]([CH2:11][CH:10]([C:5]2[CH:6]=[CH:7][C:8]([F:9])=[C:3]([C:1]#[N:2])[C:4]=2[CH3:28])[OH:27])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:14]1)(=[O:44])[CH3:42]

Participants

8

Reactant 4

HCID 8471TriethylamineHCID 31297Methanesulfonyl chlorideHCID 23670855Potassium ethanethioateHCID 71272768(3S)-tert-butyl 4-(2-(3-cyano-4-fluoro-2-methylphenyl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate

Product 1

HCID 86727057(3S)-tert-butyl 3-(acetylthiomethyl)-4-(2-(3-cyano-4-fluoro-2-methylphenyl)-2-hydroxyethyl)piperazine-1-carboxylate

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

(3S)-tert-butyl 4-(2-(3-cyano-4-fluoro-2-methylphenyl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (synthesis described above, 0.090 g, 0.23 mmol) was dissolved in THF (2.3 mL) and cooled to 0° C. Triethylamine (0.038 mL, 0.274 mmol) was added followed by addition of Ms-Cl (0.020 mL, 0.252 mmol), and DMAP (2.79 mg, 0.023 mmol). The ice bath was removed and stirring was continued for 2 hours. The reaction mixture was then concentrated under reduced pressure. The resulting material was re-dissolved in DMSO (2 mL) and treated with potassium thioacetate (0.035 g, 0.306 mmol). The reaction mixture was stirred at room temperature under nitrogen overnight and then heated at 45° C. for 2 h. The mixture was diluted with ethyl acetate and washed with water (3 times) and brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography (100% hexane to 80% EtOAc/Hexane) to give the desired product LC/MS: M+1=452.3.

Workup

  1. customThe ice bath was removed
  2. concentrationThe reaction mixture was then concentrated under reduced pressure
  3. dissolutionThe resulting material was re-dissolved in DMSO (2 mL)
  4. stirringThe reaction mixture was stirred at room temperature under nitrogen overnight
  5. temperatureheated at 45° C. for 2 h
  6. washwashed with water (3 times) and brine
  7. dry with materialdried (Na2SO4)
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe crude product was purified by column chromatography (100% hexane to 80% EtOAc/Hexane)

Sources & evidence

ORD record
ord-76bfe3227d9640bfb4494d1d9e8656e4
Source dataset
uspto-grants-2015_12
Patent number
US09206199B2

Reaction notes

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