Acetic Acid → rel-(3S,4S)-4-[(S)-1-(2,4-dimethoxy-benzylamino)-1-(2-fluoro-phenyl)-ethyl]-tetrahydro-furan-3-ol

HRID 2178197Notes

Reaction equation

HRID 2178197 reaction equation
C([Si](C)(C)[O:6][C@@H:7]1[CH2:11][O:10][CH2:9][C@@H:8]1[C@:12]([NH2:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[CH3:13])(C)(C)C.[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:27]=1[CH:28]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCCl>[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:27]=1[CH2:28][NH:21][C@@:12]([C@H:8]1[CH2:9][O:10][CH2:11][C@H:7]1[OH:6])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[CH3:13]

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 691752,4-Dimethoxybenzaldehyde2×HCID 5049666Sodium triacetoxyborohydride2×HCID 11726816Tetrabutylammonium Fluoride Trihydrate2×HCID 68158175rel-(S)-1-[(3S,4S)-4-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furan-3-yl]-1-(2-fluoro-phenyl)-ethylamine

Product 1

HCID 70654454rel-(3S,4S)-4-[(S)-1-(2,4-dimethoxy-benzylamino)-1-(2-fluoro-phenyl)-ethyl]-tetrahydro-furan-3-olYield 76%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Conditions

Temperature
0 °C

Procedure

Under an atmosphere of argon, a solution of rel-(S)-1-[(3S,4S)-4-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furan-3-yl]-1-(2-fluoro-phenyl)-ethylamine (8.13 g, 23.9 mmol) in 1,2-dichloroethane (80 ml) was treated with 2,4-dimethoxybenzaldehyde (3.98 g, 23.9 mmol), sodium triacetoxyborohydride (10.2 g, 47.9 mmol) and acetic acid (1.37 ml, 23.9 mmol). The reaction mixture was stirred overnight. In order to complete the reaction, 2,4-dimethoxybenzaldehyde (1.99 g, 12.0 mmol) and sodium triacetoxyborohydride (5.08 g, 23.9 mmol) were added and the mixture was stirred overnight. Thereafter, the reaction mixture was cooled to 0° C. and tetrabutylammonium fluoride trihydrate (7.56 g, 23.9 mmol) was added. The mixture was allowed to reach room temperature while stirring for 4 hours. In order to complete the reaction, tetrabutylammonium fluoride trihydrate (2.27 g, 7.18 mmol) was added again, and stirring continued for 4 days. For the workup, the reaction mixture was extracted twice with a mixture of a saturated solution of sodium hydrogencarbonate and dichloromethane. The combined organic layers were dried over sodium sulphate and evaporated. The residue was purified by flash chromatography on silica gel using a gradient of heptane and ethyl acetate=100:0 to 50:50 as the eluent. The rel-(3S,4S)-4-[(S)-1-(2,4-dimethoxy-benzylamino)-1-(2-fluoro-phenyl)-ethyl]-tetrahydro-furan-3-ol (6.8 g, 76% yield) was obtained as a colorless amorphous material.

Workup

  1. additionwere added
  2. stirringthe mixture was stirred overnight
  3. customto reach room temperature
  4. stirringwhile stirring for 4 hours
  5. additionwas added again
  6. stirringstirring
  7. waitcontinued for 4 days
  8. extractionFor the workup, the reaction mixture was extracted twice with a mixture of a saturated solution of sodium hydrogencarbonate and dichloromethane
  9. dry with materialThe combined organic layers were dried over sodium sulphate
  10. customevaporated
  11. customThe residue was purified by flash chromatography on silica gel using a gradient of heptane and ethyl acetate=100:0 to 50:50 as the eluent

Sources & evidence

ORD record
ord-ce8c68d65423450ea8a9a7b70a23a536
Source dataset
uspto-grants-2015_06
Patent number
US09067924B2

Reaction notes

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