Tetrahydrofuran → (1S,2S)-[3-Chloro-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-carbamic acid tert-butyl ester

HRID 1869711

Reaction equation

HRID 1869711 reaction equation
[Cl:1][CH2:2][C:3](=[O:22])[C@@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[CH:7]=1.C1COCC1.[BH4-].[Na+]>C(O)C>[Cl:1][CH2:2][C@@H:3]([OH:22])[C@@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:5][C:6]1[CH:7]=[C:8]([F:13])[CH:9]=[C:10]([F:12])[CH:11]=1

Participants

5

Reactant 3

HCID 8028TetrahydrofuranHCID 4311764Sodium borohydrideHCID 9923728tert-butyl (1S)-3-chloro-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate

Product 1

HCID 11473133(1S,2S)-[3-Chloro-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-carbamic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

To a 250 mL 3-neck round bottom flask equipped with magnetic stir bar, nitrogen inlet and thermocouple, is added tert-butyl (1S)-3-chloro-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate (III, EXAMPLE 2, 4.4 g, 0.0132 moles, 1 equivalent) followed by THF (20 mL) and ethanol (30 mL) then cooled to −78°. Once the mixture is cooled, sodium borohydride (2.0 g, 0.0527 moles, 4 equivalents) is added as a solid portion wise over 30 min keeping the internal temperature below −70°. Once this addition is complete, the contents are stirred for 2 hr at −78° then warmed to 0° and stirred an additional 1 hr. The mixture is quenched by the addition of saturated potassium bisulfate (15 mL) and water (15 mL). This slurry is stirred for 30 min at 20-250 then concentrated under reduced pressure to half its volume. The mixture is then cooled to 0° and stirred for 30 min. After this time, the resultant solids are collected by filtration and washed with water (2×50 mL) then dried under reduced pressure at 50° to give crude product. A syn/anti ratio of 4-9:1 has been observed. The desired product is recrystallized from hexanes/ethanol (25/1) to give the title compound, mp=149°; NMR (DMSO-d6) δ 6.89-7.16, 5.61, 3.64-3.83, 3.19, 2.69 and 1.41; CMR (DMSO-d6) δ 163.67, 161.24, 155.44, 112.70, 101.55, 78.04, 72.99, 54.29, 48.24, 35.97 and 28.37.

Workup

  1. customTo a 250 mL 3-neck round bottom flask equipped with magnetic stir bar, nitrogen inlet
  2. temperaturethen cooled to −78°
  3. temperatureOnce the mixture is cooled
  4. customthe internal temperature below −70°
  5. additionOnce this addition
  6. temperaturethen warmed to 0°
  7. stirringstirred an additional 1 hr
  8. customThe mixture is quenched by the addition of saturated potassium bisulfate (15 mL) and water (15 mL)
  9. stirringThis slurry is stirred for 30 min at 20-250
  10. concentrationthen concentrated under reduced pressure to half its volume
  11. temperatureThe mixture is then cooled to 0°
  12. stirringstirred for 30 min
  13. filtrationAfter this time, the resultant solids are collected by filtration
  14. washwashed with water (2×50 mL)
  15. customthen dried under reduced pressure at 50°
  16. customto give crude product
  17. customThe desired product is recrystallized from hexanes/ethanol (25/1)

Sources & evidence

ORD record
ord-17c9b246b0c448f393027acf142d7a97
Source dataset
uspto-grants-2009_12
Patent number
US07638646B2

Linked notes

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