Acetone → 3-(4-{[2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carbonyl]-amino}-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester

HRID 554855Notes

Reaction equation

HRID 554855 reaction equation
[BH4-].[Li+].[C:3]([O:7][C:8]([N:10]1[CH2:13][CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[S:28][C:27]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)=[N:26][C:25]=3[CH2:36][C:37](OC)=[O:38])=[O:23])=[CH:17][C:16]=2[O:41][CH3:42])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CC(C)=O.C(OCC)(=O)C>C1COCC1.O>[C:3]([O:7][C:8]([N:10]1[CH2:13][CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[S:28][C:27]([C:29]4[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=4)=[N:26][C:25]=3[CH2:36][CH2:37][OH:38])=[O:23])=[CH:17][C:16]=2[O:41][CH3:42])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]

Participants

7

Reactant 4

HCID 180AcetoneHCID 8857Ethyl AcetateHCID 4148881Lithium borohydrideHCID 674633163-(4-{[2-(4-Chloro-phenyl)-4-methoxycarbonylmethyl-thiazole-5-carbonyl]-amino}-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 592385093-(4-{[2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carbonyl]-amino}-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl esterYield 88%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

Charge to a flask under an inert atmosphere a 2 M THF solution of lithium borohydride (1140 mL, 2280 mmol) and apply ice bath cooling. Meanwhile in a separate vessel dissolve 3-(4-{[2-(4-chloro-phenyl)-4-methoxycarbonylmethyl-thiazole-5-carbonyl]-amino}-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (2058 g, 3500 mmol) in THF (12.35 L). Agitate until complete dissolution is obtained. Transfer this solution to an addition funnel and begin the slow stream addition to the reducing agent. Once the addition is complete, remove the ice bath and stir for 30-90 min. Quench the reaction by adding acetone (407 g, 7008 mmol). Stir at ambient temperature for 30 min and add ethyl acetate (8230 mL) with water (8230 mL). Separate the layers and wash the upper organic layer a second time with water (8230 mL) followed by 5% brine (8230 mL). Distill off the solvent until <5% solvent composition is THF, by adding EtOAc as needed. Reduce the volume of the slurry to 6200 mL and add heptane (2050 mL). Allow the slurry to slowly cool back to room temperature, filter the precipitate, wash with 1:1 heptane/ethyl acetate and dry to constant weight in a vacuum oven at 40° C. to obtain the title compound (88%). ES/MS m/z (35Cl) 560 [M+1]+.

Workup

  1. temperaturecooling
  2. customis obtained
  3. customTransfer this solution to an addition funnel and begin
  4. additionthe slow stream addition to the reducing agent
  5. additionOnce the addition
  6. customremove the ice bath
  7. stirringstir for 30-90 min
  8. customQuench
  9. customthe reaction
  10. stirringStir at ambient temperature for 30 min
  11. customSeparate the layers
  12. washwash the upper organic layer a second time with water (8230 mL)
  13. distillationDistill off the solvent until <5% solvent composition
  14. additionby adding EtOAc
  15. additionadd heptane (2050 mL)
  16. filtrationfilter the precipitate
  17. washwash with 1:1 heptane/ethyl acetate
  18. customdry to constant weight in a vacuum oven at 40° C.

Sources & evidence

ORD record
ord-7d7ba0e4994d4aae894ef2e1b5a4fb58
Source dataset
uspto-grants-2011_11
Patent number
US08049013B2

Reaction notes

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