Acetic Acid → HCID 66674982, compound

HRID 1617094Notes

Reaction equation

HRID 1617094 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:16]=[C:17]([CH:20]=[CH:21][C:22]=1[CH3:23])[CH:18]=O.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:18][C:17]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:15]([F:14])[CH:16]=2)[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 27745743-Fluoro-4-methylbenzaldehydeHCID 5003444Sodium cyanoborohydrideHCID 13396165diexo-3-Amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester

Product 1

HCID 66674982HCID 66674982, compoundYield 44.2%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
50 °C

Procedure

(1S,2R,3S,4R)-3-Amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 300 mg, 1.637 mmol) was suspended in ethanol (5 mL). 3-Fluoro-4-methyl-benzaldehyde (0.2 mL, 1.637 mmol) was added followed by glacial acetic acid (0.1 mL, 3.724 mmol) and 4 Å powdered molecular sieves (0.6 g). Sodium cyanoborohydride (0.593 g, 9.406 mmol) was added and the mixture was stirred under nitrogen at 50° C. for 18 h. Upon cooling, the mixture was filtered through Celite. The filtrate was diluted with half-saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (2×75 mL). The layers were separated and the organic layer was washed with saturated aqueous brine solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Further purification by flash column chromatography (Teledyne Isco RediSep column; 1st column: 0 to 25% ethyl acetate in hexanes; 2nd column: 0 to 20% ethyl acetate in hexanes) afforded the desired product, (1S,2R,3S,4R)-3-(3-fluoro-4-methyl-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (221 mg, 0.724 mmol, 44%), as a clear thick oil. 1H NMR (400 MHz, CDCl3) δ: 1.04-1.15 (2H, m), 1.21 (1H, d, J=10.1 Hz), 1.29 (3H, t, J=7.1 Hz), 1.42-1.63 (4H, m), 1.94 (1H, dt, J1=10.2 Hz, J2=2.0 Hz), 2.25 (3H, s), 2.43 (1H, d, J=3.5 Hz), 2.59 (1H, dd, J1=8.6 Hz, J2=1.6 Hz), 2.93 (1H, dd, J1=8.6 Hz, J2=1.6 Hz), 3.65 (1H, d, J=13.4 Hz), 3.79 (1H, d, J=14.2 Hz), 4.15 (2H, q, J=7.1 Hz), 6.94 (1H, d, J=7.9 Hz), 6.98 (1H, d, J=10.9 Hz), 7.08 (1H, t, J=7.8 Hz). LC-MS (ESI) calcd for C18H24FNO2 305.18, found 305.9 [M+H+].

Workup

  1. temperatureUpon cooling
  2. filtrationthe mixture was filtered through Celite
  3. additionThe filtrate was diluted with half-saturated aqueous sodium bicarbonate solution (50 mL)
  4. extractionextracted with ethyl acetate (2×75 mL)
  5. customThe layers were separated
  6. washthe organic layer was washed with saturated aqueous brine solution
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customFurther purification by flash column chromatography (Teledyne Isco RediSep column; 1st column: 0 to 25% ethyl acetate in hexanes; 2nd column: 0 to 20% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-3b6f0b92f57d4b79a8bf371f41cb4bda
Source dataset
uspto-grants-2014_07
Patent number
US08765741B2

Reaction notes

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