Triethylamine → (R)-3-tert-butoxycarbonylamino-4-[4-(4-fluoro-phenoxy)-piperidin-1-yl]butyric acid benzyl ester

HRID 1797262Notes

Reaction equation

HRID 1797262 reaction equation
[CH2:1]([O:8][C:9](=[O:22])[CH2:10][C@@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:22])[CH2:10][C@@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][N:32]1[CH2:31][CH2:30][CH:29]([O:28][C:27]2[CH:35]=[CH:36][C:24]([F:23])=[CH:25][CH:26]=2)[CH2:34][CH2:33]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 37348964-(4-Fluorophenoxy)piperidineHCID 68576795(R)-3-tert-butoxycarbonylamino-4-iodo-butyric acid benzyl ester

Product 1

HCID 68576098(R)-3-tert-butoxycarbonylamino-4-[4-(4-fluoro-phenoxy)-piperidin-1-yl]butyric acid benzyl ester

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Triphenylphosphine bound to cross-linked polystyrene resin (2.16 g, mol/g, 6.47 mmol) is suspended in dry DCM (50 ml) at ambient temperature under a nitrogen atmosphere. Iodine (1.64 g, 6.47 mmol) is added and the reaction mixture stirred for 15 minutes. Imidazole (0.50 g, 7.35 mmol) is then added and the reaction mixture is stirred for a further 15 minutes. A solution of (R)-3-.tert.-butoxycarbonylamino-4-hydroxy-butyric acid benzyl ester (prepared as described by D. Gani et al J. Chem. Soc. Perkin Trans. 1, 2513–2525, 1997 (0.909 g, 2.94 mmol) in dry DCM (10 ml) is added and the reaction mixture is stirred at reflux for 1 hour. The polymer is removed by filtration, and the filtrate is first washed with aqueous 5% sodium thiosulphate solution and then water. The organic phase is dried over MgSO4 and evaporated to yield (R)-3-tert-butoxycarbonylamino-4-iodo-butyric acid benzyl ester as a crude oil. A solution of (R)-3-tert-butoxycarbonylamino-4-iodo-butyric acid benzyl ester (1.017 g, 2.43 mmol) and 4-(4-fluoro-phenoxy)-piperidine (0.569 g, 2.916 mmol) in DMF (25 ml) is treated with triethylamine (0.406 ml, 2.916 mmol). The reaction mixture is stirred at ambient temperature for 60 hours, and then partitioned between ethylacetate and water. The ethylacetate phase is dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with 2:1 hexane/ethylacetate) to afford (R)-3-tert-butoxycarbonylamino-4-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-butyric acid benzyl ester. [MH]+ 487.1.

Workup

  1. custompartitioned between ethylacetate and water
  2. dry with materialThe ethylacetate phase is dried over MgSO4
  3. customevaporated
  4. customThe crude product is purified by flash silica chromatography (elution with 2:1 hexane/ethylacetate)

Sources & evidence

ORD record
ord-b1cb13301ff041fe923d98e3c7cfdf8a
Source dataset
uspto-grants-2006_04
Patent number
US07034042B2

Reaction notes

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