Acetic Acid → 6-(4-Methoxybenzylamino)hexan-3-ol

HRID 2268140Notes

Reaction equation

HRID 2268140 reaction equation
[BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][NH:10][C:11](=O)[CH2:12][CH2:13][CH:14]([OH:17])[CH2:15][CH3:16])=[CH:7][CH:6]=1.C(O)(=O)C>O1CCCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][CH:14]([OH:17])[CH2:15][CH3:16])=[CH:19][CH:20]=1

Participants

5

Reactant 3

HCID 176Acetic AcidHCID 4311764Sodium borohydrideHCID 12071259HEXANAMIDE, 4-HYDROXY-N-[(4-METHOXYPHENYL)METHYL]-

Product 1

HCID 120378166-(4-Methoxybenzylamino)hexan-3-ol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
22.5 °C

Procedure

Tetrahydrofuran (121 gal, 458 L) and sodium borohydride (22.154 kg, 585.6 moles) were charged to a clean and dry nitrogen purged 500 gallon glass lined tank. The suspension was allowed to stir for 30 minutes at 20-25° C. then 4-hydroxyhexanoic acid 4-methoxy-benzylamide (45.75 kg, 182 moles) was added as a solid. After 30 minutes, the reaction was cooled to 5-10° C. and over a 4 to 8 hour period a solution of acetic acid (9.1 gallons, 34.4 L) in tetrahydrofuran (12 gal, 45.4 L) was added keeping the temperature at 0-10° C. A slight nitrogen bleed was kept on the tank to help remove the hydrogen. When the addition was complete the reaction was warmed to 20-25° C. and stirred for an hour. The temperature of the reaction was slowly increased to a gentle reflux (˜66° C.) and held there for 16 hours. The reaction was quenched by the addition of 1N HCl, keeping the temperature <25° C. Excess tetrahydrofuran was removed by atmospheric distillation. Ethyl acetate was added to the resulting aqueous solution to extract unreacted amide. The acidic aqueous was then brought to pH 11 to allow the product amine to be extracted into ethyl acetate and held for use in the next step. An aliquot of the ethyl acetate solution of product was worked up to project final yield and concentration. The yield for this large scale run was 55.0%, which was less than that achieved with small scale preparations (78.8%). The large scale procedure had 12.8% unreduced amide starting material after the quench which accounted in part for the lower yield.

Workup

  1. custompurged 500 gallon glass
  2. waitAfter 30 minutes
  3. additionwas added
  4. customat 0-10° C
  5. customto help remove the hydrogen
  6. additionWhen the addition
  7. temperaturewas warmed to 20-25° C.
  8. stirringstirred for an hour
  9. temperatureThe temperature of the reaction was slowly increased to
  10. temperaturea gentle reflux (˜66° C.)
  11. waitheld there for 16 hours
  12. customThe reaction was quenched by the addition of 1N HCl
  13. customthe temperature <25° C
  14. customExcess tetrahydrofuran was removed by atmospheric distillation
  15. additionEthyl acetate was added to the resulting aqueous solution
  16. extractionto extract unreacted amide
  17. extractionto be extracted into ethyl acetate
  18. customto project final yield
  19. concentrationconcentration
  20. customThe yield for this large scale run
  21. customquench which
  22. customlower yield

Sources & evidence

ORD record
ord-399075da71354976870d40828cc73674
Source dataset
uspto-grants-2001_12
Patent number
US06326495B2

Reaction notes

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