Triphenylphosphine → 1-Methoxy-4-{(1-methoxy-piperidin-4-yloxy)-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylic acid methyl ester

HRID 1473784Notes

Reaction equation

HRID 1473784 reaction equation
C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:34][O:35][C:36]([C:38]1([N:46]([OH:59])[C:47](=[O:58])[CH2:48][C:49]2[C:54]([CH3:55])=[CH:53][C:52]([CH3:56])=[CH:51][C:50]=2[CH3:57])[CH2:43][CH2:42][N:41]([O:44][CH3:45])[CH2:40][CH2:39]1)=[O:37].[CH3:60][O:61][N:62]1[CH2:67][CH2:66][CH:65](O)[CH2:64][CH2:63]1>C1COCC1>[CH3:34][O:35][C:36]([C:38]1([N:46]([O:59][CH:65]2[CH2:66][CH2:67][N:62]([O:61][CH3:60])[CH2:63][CH2:64]2)[C:47](=[O:58])[CH2:48][C:49]2[C:50]([CH3:57])=[CH:51][C:52]([CH3:56])=[CH:53][C:54]=2[CH3:55])[CH2:39][CH2:40][N:41]([O:44][CH3:45])[CH2:42][CH2:43]1)=[O:37]

Participants

6

Reactant 4

HCID 11776TriphenylphosphineHCID 75555Diisopropyl diazene-1,2-dicarboxylateHCID 30226061-Methoxypiperidin-4-olHCID 584280024-{Hydroxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-1-methoxy-piperidine-4-carboxylic acid methyl ester

Product 1

HCID 584279971-Methoxy-4-{(1-methoxy-piperidin-4-yloxy)-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylic acid methyl ester

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of triphenylphosphine (1.11 g, 4.23 mmol) in THF (20 ml) at 0° C. was added diisopropyl azodicarboxylate (0.83 ml, 0.85 g, 4.24 mmol) dropwise and the resulting precipitate was stirred at 0° C. for 30 minutes. 4-{Hydroxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-1-methoxy-piperidine-4-carboxylic acid methyl ester (compound P3ii.3 obtained in analogy to preparation example 11, step 4) (1.3 g, 3.57 mmol) was further added in one portion, followed by a solution of 1-methoxy-piperidin-4-ol (0.53 g, 4.04 mmol) in THF (6 ml) dropwise at 0° C. The reaction mixture was stirred at room temperature for two hours and concentrated in vacuo. The residue was triturated with hexane and filtered to remove part of the insoluble triphenylphosphine oxide. The filtrate was evaporated and the residue purified by chromatography on silica gel (gradient ethyl acetate/heptane 3:7→ethyl acetate). Yield: 861 mg of pure 1-methoxy-4-{(1-methoxy-piperidin-4-yloxy)-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylic acid methyl ester (title compound P3ii.26) as a colorless gum, followed by a second fraction of compound P3ii.26 (701 mg) slightly contaminated with triphenylphosphine oxide.

Workup

  1. stirringThe reaction mixture was stirred at room temperature for two hours
  2. concentrationconcentrated in vacuo
  3. customThe residue was triturated with hexane
  4. filtrationfiltered
  5. customto remove part of the insoluble triphenylphosphine oxide
  6. customThe filtrate was evaporated
  7. customthe residue purified by chromatography on silica gel (gradient ethyl acetate/heptane 3:7→ethyl acetate)

Sources & evidence

ORD record
ord-ab62b3e6b3ee45fca83ba2f3db79a6d9
Source dataset
uspto-grants-2015_04
Patent number
US09018135B2

Reaction notes

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