4-Methylmorpholine → [(1R,2R)-1-(3-fluoro-azetidine-1-carbonyl)-2-hydroxy-propyl]-carbamic acid 9H-fluoren-9-ylmethyl ester

HRID 246200Notes

Reaction equation

HRID 246200 reaction equation
[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C@H:23]([OH:25])[CH3:24])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[F:27][CH:28]1[CH2:31][NH:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.CN1CCOCC1>C(#N)C>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C@@H:19]([C:20]([N:30]3[CH2:31][CH:28]([F:27])[CH2:29]3)=[O:21])[C@H:23]([OH:25])[CH3:24])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 81531DiisopropylethylamineHCID 6992534Fmoc-D-allo-Thr-OHHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 101250543-fluoroazetidine Hydrochloride

Product 1

HCID 71279979[(1R,2R)-1-(3-fluoro-azetidine-1-carbonyl)-2-hydroxy-propyl]-carbamic acid 9H-fluoren-9-ylmethyl esterYield 52.1%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

A 25 mL round-bottomed flask was charged with (2R,3R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-hydroxybutanoic acid (184 mg, 0.54 mmol), 3-fluoroazetidine hydrochloride (66 mg, 0.59 mmol), and HATU (242 mg, 0.64 mmol). Then added acetonitrile (1.1 mL) followed by N,N-diisopropylethylamine (0.20 mL, 1.1 mmol) and N-methylmorpholine (0.05 mL, 0.45 mmol). The reaction mixture was stirred at room temperature overnight then concentrated. The crude solid was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 10-80% EtOAc) to afford 112 mg (52%) of [(1R,2R)-1-(3-fluoro-azetidine-1-carbonyl)-2-hydroxy-propyl]-carbamic acid 9H-fluoren-9-ylmethyl ester as a white solid. MS: [M+H]+=399.

Workup

  1. concentrationthen concentrated
  2. customThe crude solid was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 10-80% EtOAc)

Sources & evidence

ORD record
ord-6db0ead717074accb339865d5d07ca5b
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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