Acetic Acid → (R)-3-(N-Cyclobutyl-N-isopropylamino)-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran

HRID 52276Notes

Reaction equation

HRID 52276 reaction equation
[F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([NH:12][CH:13]([CH3:15])[CH3:14])[CH2:7][C:6]=2[C:5]([O:16][CH3:17])=[CH:4][CH:3]=1.[C:18]1(=O)[CH2:21][CH2:20][CH2:19]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH:18]1([N:12]([C@@H:8]2[CH2:7][C:6]3[C:5]([O:16][CH3:17])=[CH:4][CH:3]=[C:2]([F:1])[C:11]=3[O:10][CH2:9]2)[CH:13]([CH3:15])[CH3:14])[CH2:21][CH2:20][CH2:19]1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 14496CyclobutanoneHCID 5003444Sodium cyanoborohydrideHCID 54036921HCID 54036921, compound

Product 1

HCID 54238615(R)-3-(N-Cyclobutyl-N-isopropylamino)-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyranYield 77%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

(R)-8-Fluoro-3-(N-isopropylamino)-5-methoxy-3,4-dihydro-2H-1-benzopyran (1.96 g, 8.19 mmol) was dissolved in anhydrous methanol (20 mL) and to this was cyclobutanone (6.1 mL, 81.9 mmol) added. The reaction was cooled (ice-bath) then sodium cyanoborohydride (2.0 g, 16.4 mmol) was added, the pH was adjusted to 4-5 with acetic acid, 3 Å molecular sieves were added and the reaction was allowed to stir at room temperature overnight. After 24 h the pH-was again adjusted to 4-5 and the reaction was allowed to stir for 3 more days. The reaction was filtered, solvent was removed in vacuo, the remains were taken into a 2M solution of NH3 and then extracted thrice with diethyl ether. The combined ether portions were dried (MgSO4) filtered, and the solvent removed in vacuo to give the crude residue. Chromatography on silica (eluent: 10% ethyl acetate/hexane) gave 1.60 g (77% yield) of the title compound as a clear oil. [α]21D =-95.1° (C=0.1; CHCl3). GC-MS (70 eV) M=293 (3%).

Workup

  1. additionadded
  2. temperatureThe reaction was cooled (ice-bath)
  3. additionwere added
  4. waitAfter 24 h the pH-was again adjusted to 4-5
  5. stirringto stir for 3 more days
  6. filtrationThe reaction was filtered
  7. customsolvent was removed in vacuo
  8. extractionextracted thrice with diethyl ether
  9. dry with materialThe combined ether portions were dried (MgSO4)
  10. filtrationfiltered
  11. customthe solvent removed in vacuo
  12. customto give the crude residue

Sources & evidence

ORD record
ord-0156f0fdc7074738ba44a836733f0b69
Source dataset
uspto-grants-1997_04
Patent number
US05616610

Reaction notes

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