Hydrochloric Acid → Ethyl (3S)-4-chloro-3-hydroxybutanoate

HRID 719073

Reaction equation

HRID 719073 reaction equation
N(CCO)(CCO)CCO.Cl.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[Cl:24][CH2:25][C:26](=[O:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C([O-])([O-])=O.[Na+].[Na+]>O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)([O-])=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.C(OCCCC)(=O)C.O>[Cl:24][CH2:25][C@@H:26]([OH:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 7618Triethanolamine2×HCID 10340Sodium CarbonateHCID 69484Ethyl 4-chloroacetoacetateHCID 107526(2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanal2×

Product 1

HCID 7019277Ethyl (3S)-4-chloro-3-hydroxybutanoateYield 85.9%

Reagents, catalysts & solvents 4

HCID 5892NadideCatalystHCID 107526(2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanalCatalystHCID 962WaterSolvent2×HCID 31272Butyl AcetateSolvent

Procedure

To a 3-necked jacketed 3 L flask equipped with a mechanical stirrer and connected to an automatic titrater by a pH electrode and a feeding tube for addition of base, was charged triethanolamine (6.6 mL) and H2O (492 mL) to make 100 mM triethanolamine solution. The pH was adjusted to 7 with 37% HCl. Then, D-Glucose (125 g) was added. The water circulating to the flask jacket was set to 30° C. After 10 minutes, ketoreductase SEQ ID NO: 2 (5.7 g) and glucose dehydrogenase S06 SEQ ID NO: 10 (3.1 g) powder were added. After 10 minutes, β-NAD (125 mg) was added and the resulting mixture was allowed to stir for 5 minutes. Then, butyl acetate (250 mL) was charged. Using an addition funnel, 2.4 M ethyl 4-chloroacetoacetate (250 mL, 100 g in 167 mL of butyl acetate) was slowly added over 3 hrs. The pH was maintained at 7 by the automatic titrater by the addition of 2 M Na2CO3 (152 mL) over 15 hrs. Subsequently, gas chromatography of a reaction sample showed complete conversion to product. Celite (16 g) was added and the reaction mixture was allowed to stir for 10 minutes. The solution was filtered through a celite pad and the organic layer was separated. The aqueous layer was extracted with butyl acetate (2×200 mL). The organic layers were combined and the solvent removed under vacuum by rotary evaporation to obtain 87 g of the ethyl (S) 4-chloro-3-hydroxybutyrate. The enantiomeric excess was >99%, as determined after its conversion to ethyl (R)-4-cyano-3-hydroxybutyrate in Example 8.

Workup

  1. customTo a 3-necked jacketed 3 L flask equipped with a mechanical stirrer
  2. additionconnected to an automatic titrater by a pH electrode and a feeding tube for addition of base
  3. customwas set to 30° C
  4. waitAfter 10 minutes
  5. additionCelite (16 g) was added
  6. stirringto stir for 10 minutes
  7. filtrationThe solution was filtered through a celite pad
  8. customthe organic layer was separated
  9. extractionThe aqueous layer was extracted with butyl acetate (2×200 mL)
  10. customthe solvent removed under vacuum by rotary evaporation

Sources & evidence

ORD record
ord-e79135c10a2c48038521d092d9536023
Source dataset
uspto-grants-2006_11
Patent number
US07132267B2

Linked notes

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