Ethanol → (3R,4R)-Benzyl 4-((tert-butoxycarbonyl)amino)-3-hydroxypiperidine-1-carboxylate

HRID 1028069Notes

Reaction equation

HRID 1028069 reaction equation
C(OC(N[C@@H:9]1[C@@H:14](O)[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=O)(C)(C)C.[C:26]([O:30][C:31]([NH:33][C@H]1[C@H](O)CCN(C(OCC2C=CC=CC=2)=O)C1)=[O:32])([CH3:29])([CH3:28])[CH3:27].CCCCCCC.C([OH:60])C>>[C:26]([O:30][C:31]([NH:33][C@@H:14]1[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH2:10][C@H:9]1[OH:60])=[O:32])([CH3:29])([CH3:28])[CH3:27]

Participants

5

Reactant 4

HCID 702EthanolHCID 8900HeptaneHCID 53487823Benzyl (3R,4R)-3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylateHCID 58423176Phenylmethyl (3S,4S)-3-(((1,1-dimethylethoxy)carbonyl)amino)-4-hydroxy-1-piperidinecarboxylate

Product 1

HCID 58745562(3R,4R)-Benzyl 4-((tert-butoxycarbonyl)amino)-3-hydroxypiperidine-1-carboxylate

Procedure

A solution of (+/−) benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (1.0 equiv.) in saturated ammonium hydroxide aqueous solution and ethanol (1:1, 0.05 M solution) in a sealed steel bomb was heated to 70° C. for 5 h. After all volatile materials were removed by N2 gas stream, ethyl acetate and water were added for work-up. The crude regioisomeric mixture, benzyl 3-amino-4-hydroxypiperidine-1-carboxylate and benzyl 4-amino-3-hydroxypiperidine-1-carboxylate was reacted with Boc2O (1.0 equiv.) and triethylamine (1.0 equiv.) in dichloromethane (0.1 M solution). After stirred for 2 h at room temperature, the reaction mixture was extracted with dichloromethane. The polar (+/−)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate and nonpolar (+/−)-benzyl 4-(tert-butoxycarbonylamino)-3-hydroxypiperidine-1-carboxylate were obtained by flash column chromatography (20% to 40% EtOAc in hexanes, 28%, 51% each). LCMS (m/z): 351.1 (MH+), Rt=0.81 min, LCMS (m/z): 351.1 (MH+), Rt=0.83 min. The enantiomerically pure (3S,4S)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate and (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate were resolved by chiral HPLC (For analysis Rt=6.8 min and 9.1 min respectively; n-heptane:ethanol=70:30 (v:v), Chiralpak AD-H prep 250×4.6 mm at 1 mL/min. For preparative separation, n-heptane:ethanol=80:20 (v:v), Chiralpak AS 50×500 mm. at 90 mL/min).

Workup

  1. customFor analysis Rt=6.8 min and 9.1 min
  2. customFor preparative separation, n-heptane

Sources & evidence

ORD record
ord-55d0f1106daf479099f1dda9cfd0df7b
Source dataset
uspto-grants-2014_05
Patent number
US08735424B2

Reaction notes

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