Sulfuric acid magnesium salt (1:1) → (R)-2-((S)-2-hydroxy-1-phenylethylamino)-2-(1-methylcyclopropyl)acetonitrile

HRID 1898526Notes

Reaction equation

HRID 1898526 reaction equation
[CH3:1][C:2]1([CH:5]=O)[CH2:4][CH2:3]1.[NH2:7][C@@H:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][OH:10].[O-]S([O-])(=O)=O.[Mg+2].C[Si](C)(C)[C:25]#[N:26]>C(Cl)(Cl)Cl>[OH:10][CH2:9][C@@H:8]([NH:7][C@H:5]([C:2]1([CH3:1])[CH2:3][CH2:4]1)[C:25]#[N:26])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1

Participants

6

Reactant 4

HCID 24083Sulfuric acid magnesium salt (1:1)HCID 82115Trimethylsilyl cyanideHCID 1347972-Amino-2-phenylethan-1-olHCID 101976191-Methylcyclopropane-1-carbaldehyde

Product 1

HCID 67386387(R)-2-((S)-2-hydroxy-1-phenylethylamino)-2-(1-methylcyclopropyl)acetonitrileYield 22%

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent

Procedure

To a solution of 1-methyl-cyclopropanecarbaldehyde (1.85 g, 22.0 mmol) in CHCl3 (30 mL) was added (S)-2-amino-2-phenylethanol (2.74 g, 20.0 mmol) and MgSO4 (3 g). The cloudy reaction mixture was stirred at room temperature for 3 hr then filtered, rinsing with CHCl3 (10 mL). Cooled to 0° C. and slowly added trimethylsilanecarbonitrile (5.0 ml, 39.9 mmol). The orange reaction mixture was stirred at 0° C. for 1 hr then allowed to warm to room temperature overnight. The reaction was quenched with 1.0 M HCl and stirred vigorously for 5 min then neutralized with 10% aqueous NaOH and extracted with CH2Cl2. The combined organics were dried over MgSO4 and concentrated to a light orange oil. NMR analysis showed that some TMS-ether remained. The crude product was treated with 10 mL of 3.0 M aqueous HCl for 10 min at which time TLC verified that the silyl group was removed. Extracted with CH2Cl2 (2×), dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (10-30% EtOAc/hexanes) to isolate 1.0 g (22%) of (R)-2-((S)-2-hydroxy-1-phenylethylamino)-2-(1-methylcyclopropyl)acetonitrile as a colorless oil and a single diastereomer.

Workup

  1. customThe cloudy reaction mixture
  2. filtrationthen filtered
  3. washrinsing with CHCl3 (10 mL)
  4. temperatureCooled to 0° C.
  5. stirringThe orange reaction mixture was stirred at 0° C. for 1 hr
  6. temperatureto warm to room temperature overnight
  7. customThe reaction was quenched with 1.0 M HCl
  8. stirringstirred vigorously for 5 min
  9. extractionextracted with CH2Cl2
  10. dry with materialThe combined organics were dried over MgSO4
  11. concentrationconcentrated to a light orange oil
  12. additionThe crude product was treated with 10 mL of 3.0 M aqueous HCl for 10 min at which time TLC
  13. customwas removed
  14. extractionExtracted with CH2Cl2 (2×)
  15. dry with materialdried over MgSO4
  16. concentrationconcentrated
  17. customThe residue was purified by SiO2 chromatography (10-30% EtOAc/hexanes)

Sources & evidence

ORD record
ord-553f66f0282048338819d6fee0e62d87
Source dataset
uspto-grants-2013_08
Patent number
US08518945B2

Reaction notes

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