Potassium Carbonate → (3S,4S)-Benzyl 3-((tert-butoxycarbonyl)amino)-4-(hydroxymethyl)pyrrolidine-1-carboxylate

HRID 1487315Notes

Reaction equation

HRID 1487315 reaction equation
CO[N:3]=[C:4]1[CH2:8][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:6][CH:5]1[C:19]([O:21]C)=O.B.C1COCC1.C([O-])([O-])=O.[K+].[K+].[O:35](C(OC(C)(C)C)=O)[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=O>C1COCC1.CCOC(C)=O.O>[C:39]([O:38][C:36]([NH:3][C@H:4]1[C@@H:5]([CH2:19][OH:21])[CH2:6][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:8]1)=[O:35])([CH3:42])([CH3:41])[CH3:40]

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 90495Di-tert-butyl dicarbonateHCID 2723981Borane;tetrahydrofuranHCID 86707895HCID 86707895, compound

Product 1

HCID 23635905(3S,4S)-Benzyl 3-((tert-butoxycarbonyl)amino)-4-(hydroxymethyl)pyrrolidine-1-carboxylateYield 38%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 1-benzyl 3-methyl 4-(methoxyimino)pyrrolidine-1,3-dicarboxylate (12.6 g, 41.1 mmol) in THF (100 mL) at −78° C. was added borane THF complex (1M in THF, 148 mL, 148 mmol) dropwise and stirred for 1.5 hrs, and then it was warmed to 0° C. and stirred for 2 hrs and further warmed up to RT and stirred for 16 hrs. The reaction was quenched with water at 0° C. until effervescence ceased, and to it was added K2CO3 (5.68 g, 41.1 mmol). The reaction mixture was warmed up to RT and stirred for 1 hr. (BOC)2O (11.46 mL, 49.4 mmol) was added. The reaction mixture was stirred at RT for 16 hrs. The reaction mixture was added 200 mL of water and 500 mL of EtOAc and stirred for 10 minutes. The organic phase was separated and washed with 200 mL of brine, dried over Na2SO4, and then it was filtered, concentrated and purified by silica gel chromatography, eluting with 0-70% ethyl acetate in hexanes, to give the racemic title compound (5.46 g, 38% yield). 1H NMR (400 MHz, chloroform-d) δ 7.41-7.30 (m, 5H), 5.15 (d, J=1.3 Hz, 2H), 4.86-4.72 (m, 1H), 4.30 (br. s., 1H), 3.94-3.85 (m, 1H), 3.66 (dd, J=11.9, 5.1 Hz, 2H), 3.59-3.44 (m, 3H), 2.96 (q, J=11.4 Hz, 1H), 2.57 (br. s., 1H), 1.50-1.44 (m, 9H). MS(ES+) m/z: 351.1 (M+H); HPLC retention time: 2.79 min (analytical HPLC Method B).

Workup

  1. stirringstirred for 2 hrs
  2. temperaturefurther warmed up to RT
  3. stirringstirred for 16 hrs
  4. customThe reaction was quenched with water at 0° C. until effervescence
  5. temperatureThe reaction mixture was warmed up to RT
  6. stirringstirred for 1 hr
  7. stirringThe reaction mixture was stirred at RT for 16 hrs
  8. stirringstirred for 10 minutes
  9. customThe organic phase was separated
  10. washwashed with 200 mL of brine
  11. dry with materialdried over Na2SO4
  12. filtrationit was filtered
  13. concentrationconcentrated
  14. custompurified by silica gel chromatography
  15. washeluting with 0-70% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-4bb7a58bbe524b36b444535ac1e1377c
Source dataset
uspto-grants-2016_08
Patent number
US09428511B2

Reaction notes

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