Acetic Acid → (1S,2R,3S,4R)-3-(4-fluorobenzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester

HRID 421453Notes

Reaction equation

HRID 421453 reaction equation
[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH2:12])[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=2)[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 680234-FluorobenzaldehydeHCID 5003444Sodium cyanoborohydrideHCID 13396165diexo-3-Amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester

Product 1

HCID 66658077(1S,2R,3S,4R)-3-(4-fluorobenzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl esterYield 95.1%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of (1S,2R,3S,4R)-3-amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (1.15 g, 6.28 mmol) in ethanol (30 mL) was added 4-fluorobenzaldehyde (0.68 mL, 6.31 mmol), glacial acetic acid (0.4 mL, 6.99 mmol), and sodium cyanoborohydride (1.04 g, 15.7 mmol) at 25° C. After stirring for 3 h, the mixture was diluted with ethyl acetate (50 mL) and quenched with saturated aqueous sodium bicarbonate solution (50 mL) for 0.5 h. The mixture was filtered through Celite. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). When all solvent was removed, a solid was formed. The solid was filtered, washed with water, and dried in vacuo to afford the desired product, (1S,2R,3S,4R)-3-(4-fluorobenzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (1.74 g, 5.97 mmol, 95%), as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.05-1.16 (2H, m), 1.21 (1H, dt, J1=8.0 Hz, J2=1.6 Hz), 1.27 (3H, t, J=7.4 Hz), 1.45-1.61 (2H, m), 1.94 (1H, dt, J1=10.1 Hz, J2=1.9 Hz), 2.28 (1H, d, J=3.9 Hz), 2.43 (1H, d, J=3.3 Hz), 2.60 (1H, dd, J1=8.8 Hz, J2=1.5 Hz), 2.94 (1H, d, J=7.8 Hz), 3.66 (1H, d, J=13.2 Hz), 3.80 (1H, d, J=13.5 Hz), 4.13 (2H, q, J=7.0 Hz), 6.97 (2H, t, J=8.5 Hz), 7.26 (2H, t, J=7.1 Hz).

Workup

  1. customquenched with saturated aqueous sodium bicarbonate solution (50 mL) for 0.5 h
  2. filtrationThe mixture was filtered through Celite
  3. customThe organic layer was separated
  4. extractionthe aqueous layer was extracted with ethyl acetate (2×50 mL)
  5. customWhen all solvent was removed
  6. customa solid was formed
  7. filtrationThe solid was filtered
  8. washwashed with water
  9. customdried in vacuo

Sources & evidence

ORD record
ord-addd2af53b534d1991f13a178ee180f8
Source dataset
uspto-grants-2012_01
Patent number
US08097613B2

Reaction notes

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