(1R,3S,5R)-2-(tert-Butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid → (1R,3S,5R)-tert-butyl 3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

HRID 1471124Notes

Reaction equation

HRID 1471124 reaction equation
[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](O)=[O:15])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[OH:15][CH2:14][C@@H:13]1[CH2:12][C@@H:11]2[C@@H:9]([CH2:10]2)[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]

Participants

3

Reactant 1

HCID 11020613(1R,3S,5R)-2-(tert-Butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid

Product 1

HCID 57611064(1R,3S,5R)-tert-butyl 3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylateYield 91.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (9.85 g, 43.3 mmol) in THF (200 mL) at 0° C. was added dropwise borane-methyl sulfide complex (282 mL, 563 mmol) over 30 min. The ice bath was removed, the mixture was stirred for 1 h and then heated at reflux for 2 h. The mixture was cooled to 0° C., slowly quenched with methanol (˜200 mL) and concentrated under vacuum. The residue was dissolved in DCM and washed with water (emulsion), 1N HCl, sat NaHCO3 aq, and brine. The organic layer was dried over Na2SO4, filtered and concentrated to yield (1R,3S,5R)-tert-butyl 3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (8.43 g, 39.5 mmol, 91% yield) as colorless oil. LC-MS retention time 1.398 min; m/z 236.20 [M+Na]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min and an analysis time of 4 min where Solvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 90% methanol/10% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 3.72-3.79 (m, 1H), 3.52-3.64 (m, 3H), 3.15-3.24 (m, 1H), 2.00-2.08 (m, 1H), 1.62-1.72 (m, 1H), 1.54-1.62 (m, 1H), 1.45-1.51 (m, 9H), 0.84 (br s, 1H), 0.36 (td, J=5.0, 2.4 Hz, 1H).

Workup

  1. customThe ice bath was removed
  2. temperatureheated
  3. temperatureat reflux for 2 h
  4. customslowly quenched with methanol (˜200 mL)
  5. concentrationconcentrated under vacuum
  6. dissolutionThe residue was dissolved in DCM
  7. washwashed with water (emulsion), 1N HCl
  8. dry with materialThe organic layer was dried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-fd247680ab72408991c09a16e725f639
Source dataset
uspto-grants-2015_04
Patent number
US09006455B2

Reaction notes

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