Triethylamine → Benzyl 4-((tert-butoxycarbonyl)amino)-3-hydroxypiperidine-1-carboxylate

HRID 1920145Notes

Reaction equation

HRID 1920145 reaction equation
C12OC1CCN(C(OCC1C=CC=CC=1)=O)C2.[NH2:18][CH:19]1[CH:24]([OH:25])[CH2:23][CH2:22][N:21]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:20]1.[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])[CH2:39][CH:38]1[OH:53].[CH3:54][C:55]([O:58][C:59](O[C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])=[O:60])([CH3:57])[CH3:56].C(N(CC)CC)C>[OH-].[NH4+].C(O)C.ClCCl>[C:55]([O:58][C:59]([NH:18][CH:19]1[CH:24]([OH:25])[CH2:23][CH2:22][N:21]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:20]1)=[O:60])([CH3:57])([CH3:56])[CH3:54].[C:65]([O:64][C:62]([NH:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[O:44])[CH2:39][CH:38]1[OH:53])=[O:63])([CH3:66])([CH3:67])[CH3:68]

Participants

10

Reactant 5

HCID 8471TriethylamineHCID 90495Di-tert-butyl dicarbonateHCID 13186888Benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylateHCID 17917905Benzyl 4-amino-3-hydroxypiperidine-1-carboxylateHCID 66706179Benzyl 3-amino-4-hydroxypiperidine-1-carboxylate

Product 2

HCID 57525701Benzyl 4-((tert-butoxycarbonyl)amino)-3-hydroxypiperidine-1-carboxylateHCID 67972312Benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxypiperidine-1-carboxylate

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 6344DichloromethaneSolventHCID 14923Ammonium HydroxideSolvent

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. customAfter all volatile materials were removed by N2 gas stream, ethyl acetate and water
  2. additionwere added for work-up
  3. extractionthe reaction mixture was extracted with dichloromethane

Sources & evidence

ORD record
ord-0f299282d5754046a779a4de9a903d08
Source dataset
uspto-grants-2012_05
Patent number
US08168794B2

Reaction notes

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