Sodium triacetoxyborohydride → (1R,5S,6R)-5-(5-((cyclobutylmethyl)amino)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine

HRID 1526643Notes

Reaction equation

HRID 1526643 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@@:8]2([CH:16]([F:18])[F:17])[C@H:14]3[C@H:12]([CH2:13]3)[O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH:20]1([CH:24]=O)[CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:20]1([CH2:24][NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]3([CH:16]([F:17])[F:18])[C@@H:14]4[C@@H:12]([CH2:13]4)[O:11][C:10]([NH2:15])=[N:9]3)[CH:7]=2)[CH2:23][CH2:22][CH2:21]1

Participants

5

Reactant 3

HCID 5049666Sodium triacetoxyborohydrideHCID 12431621Cyclobutanecarbaldehyde2×HCID 90414662(1S,5R,6S)-5-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine

Product 1

HCID 118232920(1R,5S,6R)-5-(5-((cyclobutylmethyl)amino)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

To a solution of (1R,5S,6R)-5-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine (16g-B, 50 mg, 0.184 mmol) in 1,2-dichloroethane (1.2 mL) was added cyclobutanecarbaldehyde (15.51 mg, 0.184 mmol) and sodium triacetoxyborohydride (0.033 mL, 0.221 mmol). After addition, the mixture was then stirred at room temperature for 3 h. Additional cyclobutanecarbaldehyde (15.51 mg, 0.184 mmol) was added and the mixture was stirred at room temperature for additional 30 min. The mixture was quenched with saturated NaHCO3 and extracted with DCM (1×6 mL). The organic layer was collected, dried over MgSO4, and concentrated. The residue was then dissolved in MeOH and solution mixture was purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give a desired product, which was dissolved in MeOH. The solution was loaded onto a PL-HCO3 MP SPE 200 mg/6 mL column and eluted with MeOH (2×2 mL). The combined eluates were concentrated and dried in vacuo to give 30 mg of the title compound as a light yellow solid. MS m/z=340.1 [M+H]+

Workup

  1. additionAfter addition
  2. stirringthe mixture was stirred at room temperature for additional 30 min
  3. customThe mixture was quenched with saturated NaHCO3
  4. extractionextracted with DCM (1×6 mL)
  5. customThe organic layer was collected
  6. dry with materialdried over MgSO4
  7. concentrationconcentrated
  8. dissolutionThe residue was then dissolved in MeOH
  9. customsolution mixture was purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA)

Sources & evidence

ORD record
ord-c6f3e7fdcdaf425cbf824f00c3a24e3e
Source dataset
uspto-grants-2015_07
Patent number
US09085576B2

Reaction notes

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