Isopropanol → 2-(Hydroxymethyl)hexanoic acid

HRID 271973Notes

Reaction equation

HRID 271973 reaction equation
C([O:3][C:4](=[O:13])[CH:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:6](O)=[O:7])C.C(O)(C)C.[BH4-].[Li+]>O1CCCC1>[CH2:9]([CH:5]([CH2:6][OH:7])[C:4]([OH:13])=[O:3])[CH2:10][CH2:11][CH3:12]

Participants

5

Reactant 3

HCID 3776IsopropanolHCID 5832772-(Ethoxycarbonyl)hexanoic acidHCID 4148881Lithium borohydride

Product 1

HCID 166556012-(Hydroxymethyl)hexanoic acidYield 543.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
16.5 °C

Procedure

A 12 L, 4-necked, round-bottomed flaks, equipped with a mechanical stirrer, digital thermometer, and nitrogen inlet-outlet is charged with 2-butyl-propanedioic acid monoethyl ester (3, 450.0 g, 2.39 mol) and isopropanol (4.5 L). The solution is cooled to an internal temperature at 15-18° C. and a 2 M solution of lithium borohydride (2.4 L, 4.8 mol) in tetrahydrofuran is added over a period of 1.5 hours while maintaining the internal temperature at 15-25° C. The stirring is continued for an additional 3 h. The reaction mixture is cooled to an internal temperature at 10-13° C. and quenched by the addition of 2 N HCl (2.4 L) over a period of 1 hour while maintaining the internal temperature at 10-25° C. The reaction mixture is concentrated at 35-40° C. (20 mbar) to collect ˜7.5 L of the solvent to obtain a suspension (˜1.9 kg). This suspension is diluted with water (2.0 L) and ethyl acetate (2.5 L) and the biphasic mixture is stirred for 1 hour. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2.0 L). The combined organic layers are washed with 20% aqueous solution of sodium chloride (1.0 L) and concentrated under vacuum (20 mbar) until no further solvent distills to afford crude (±)-2-butyl-3-hydroxypropionic acid (4, 349.4 g, 100%) as a colorless liquid, which is used as such in the next step.

Workup

  1. customA 12 L, 4-necked, round-bottomed flaks, equipped with a mechanical stirrer
  2. temperaturewhile maintaining the internal temperature at 15-25° C
  3. temperatureThe reaction mixture is cooled to an internal temperature at 10-13° C.
  4. customquenched by the addition of 2 N HCl (2.4 L) over a period of 1 hour
  5. temperaturewhile maintaining the internal temperature at 10-25° C
  6. concentrationThe reaction mixture is concentrated at 35-40° C. (20 mbar)
  7. customto collect ˜7.5 L of the solvent

Sources & evidence

ORD record
ord-566547520d0548a19fbd81af5fac7943
Source dataset
uspto-grants-2008_11
Patent number
US07452999B2

Reaction notes

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