Acetic Acid → 1,1-Dimethylethyl 6-cyano-3,5-dihydroxyhexanoate

HRID 2304035Notes

Reaction equation

HRID 2304035 reaction equation
[C:1]([CH2:3][CH:4]([OH:16])[CH2:5][C:6](=[O:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].C(O)(=O)C.[BH4-].[Na+].[OH-].[Na+]>O1CCCC1.C(B(CC)CC)C.CO>[C:1]([CH2:3][CH:4]([OH:16])[CH2:5][CH:6]([OH:15])[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])#[N:2]

Participants

8

Reactant 4

HCID 176Acetic AcidHCID 14798Sodium HydroxideHCID 4311764Sodium borohydrideHCID 11637184Tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate

Product 1

HCID 222829971,1-Dimethylethyl 6-cyano-3,5-dihydroxyhexanoate

Reagents, catalysts & solvents 3

HCID 887MethanolSolvent2×HCID 7357TriethylboraneSolventHCID 8028TetrahydrofuranSolvent

Procedure

Crude 5R 1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate (about 150 moles) from Step (1) is dissolved in 325 L of tetrahydrofuran containing about 20 kg of triethylborane, stirred for about 2 hours at room temperature, cooled to ±75° C.±20° C. and diluted with 25 L of methanol and 8 kg of acetic acid. Sodium borohydride (8 kg) as a solution in methanol and aqueous sodium hydroxide is added slowly. After the addition, the reaction mixture is warmed to 0° C.±25° C. The reaction mixture is optionally quenched by the addition of 3 kcg of acetic acid and 10 L of methanol and concentrated by vacuum distillation, saving the distillate. The residue is dissolved in methanol and acetic acid, optionally diluted with water, and concentrated by vacuum distillation, keeping this distillate separate from the first one. The residue is dissolved in methanol and concentrated by vacuum distillation. The residue is dissolved in a mixture of water and ethyl acetate, and the aqueous layer separated. The organic layer is concentrated by vacuum distillation. The residue is dissolved in methanol and acetic acid and concentrated by vacuum distillation. The residue is dissolved in ethyl acetate and concentrated by vacuum distillation affording crude [R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate.

Workup

  1. temperaturecooled to ±75° C.±20° C.
  2. additionAfter the addition
  3. temperaturethe reaction mixture is warmed to 0° C.±25° C
  4. customThe reaction mixture is optionally quenched by the addition of 3 kcg of acetic acid and 10 L of methanol
  5. concentrationconcentrated by vacuum distillation
  6. dissolutionThe residue is dissolved in methanol
  7. additionacetic acid, optionally diluted with water
  8. concentrationconcentrated by vacuum distillation
  9. customthis distillate separate from the first one
  10. dissolutionThe residue is dissolved in methanol
  11. concentrationconcentrated by vacuum distillation
  12. dissolutionThe residue is dissolved in a mixture of water and ethyl acetate
  13. customthe aqueous layer separated
  14. concentrationThe organic layer is concentrated by vacuum distillation
  15. dissolutionThe residue is dissolved in methanol
  16. concentrationacetic acid and concentrated by vacuum distillation
  17. dissolutionThe residue is dissolved in ethyl acetate
  18. concentrationconcentrated by vacuum distillation

Sources & evidence

ORD record
ord-76090393d199421584b025e5bbca5b67
Source dataset
uspto-grants-2002_08
Patent number
US06433213B1

Reaction notes

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