4-Methylmorpholine → 1,1-Dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-hydroxybutanoate

HRID 1160390Notes

Reaction equation

HRID 1160390 reaction equation
ClC(OCC(C)C)=O.[Cl:9][C:10]1[CH:11]=[C:12]([NH:18][C@@H:19]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20](O)=[O:21])[CH:13]=[CH:14][C:15]=1[C:16]#[N:17].CN1CCOCC1.[BH4-].[Na+]>C1COCC1.O>[Cl:9][C:10]1[CH:11]=[C:12]([NH:18][C@H:19]([CH2:20][OH:21])[CH2:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH:13]=[CH:14][C:15]=1[C:16]#[N:17]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 4311764Sodium borohydrideHCID 59516164HCID 59516164, compound

Product 1

HCID 595162281,1-Dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-hydroxybutanoateYield 64.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-10 °C

Procedure

A solution of isobutyl chloroformate (2.01 g, 14.8 mmol) in THF (5 mL) was added dropwise to a solution of (2S)-2-[(3-chloro-4-cyanophenyl)amino]-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoic acid (4.57 g, 14.1 mmol) and NMM (1.56 g, 15.5 mmol) in THF (50 mL) at −10° C. After stirring for 30 min, the reaction was filtered through a pad Celite and the filtrate was cooled to −10° C. To the cold filtrate, a solution of NaBH4 (0.80 g, 21 mmol) in H2O (10 mL) was added slowly and the reaction solution was stirred at −10° C. for 15 min and then at room temperature for 45 min. The reaction was quenched with aqueous NH4Cl and extracted with Et2O (2×). The organic extracts were washed with 5% Na2CO3, cold 0.1N HCl and H2O, dried over Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography with 0% MeOH in CH2Cl2 grading to 3% MeOH in CH2Cl2 to afford the titled product (2.83 g, 64%) as a solid. 1H-NMR (CDCl3) δ: 1.45 (9H, s), 2.61 (2H, m), 3.79 (2H, d, J=4.4 Hz), 3.93 (1H, m), 6.55 (1H, dd, J=8 Hz, 4 Hz), 6.72 (1H, d, J=2 Hz), 7.41 (1H, d, J=8.8 Hz). LC-MS (ES) m/e 311.5 (M+H)+.

Workup

  1. filtrationthe reaction was filtered through a pad Celite
  2. stirringthe reaction solution was stirred at −10° C. for 15 min
  3. waitat room temperature for 45 min
  4. customThe reaction was quenched with aqueous NH4Cl
  5. extractionextracted with Et2O (2×)
  6. washThe organic extracts were washed with 5% Na2CO3, cold 0.1N HCl and H2O
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe residue was purified via silica gel chromatography with 0% MeOH in CH2Cl2 grading to 3% MeOH in CH2Cl2

Sources & evidence

ORD record
ord-c85870af394740f2855f297c6ef05101
Source dataset
uspto-grants-2010_10
Patent number
US07816395B2

Reaction notes

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