Tributylphosphine → (3S)-3-[1-(6-methoxy-2-methyl-3-pyridyloxy)-3-methyl-butyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 1922178Notes

Reaction equation

HRID 1922178 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]([OH:18])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21]1[N:26]=[C:25]([CH3:27])[C:24](O)=[CH:23][CH:22]=1.C(P(CCCC)CCCC)CCC.C1CCN(C(/N=N/C(N2CCCCC2)=O)=O)CC1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]([O:18][C:24]2[C:25]([CH3:27])=[N:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 5

HCID 13831TributylphosphineHCID 516892Sodium BicarbonateHCID 5702657diazenedicarboxylic acid bis(N,N-piperidide)HCID 59536621HCID 59536621, compoundHCID 59536655(3S)-3-(1-hydroxy-3-methyl-butyl)-pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 66736879(3S)-3-[1-(6-methoxy-2-methyl-3-pyridyloxy)-3-methyl-butyl]-pyrrolidine-1-carboxylic acid tert-butyl esterYield 13.8%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
70 °C

Procedure

Purge nitrogen through a solution of (3S)-3-(1-hydroxy-3-methyl-butyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (S-1) (0.5 g, 1.94 mmol) and 6-methoxy-2-methyl-pyridin-3-ol (0.41 g, 2.91 mmol) in toluene (10 mL) at room temperature for 10 minutes. Add tri-n-butylphosphine (0.73 mL, 2.91 mmol) followed by azodicarboxylic acid dipiperidide (0.59 mg, 2.91 mmol). Heat the reaction mixture to 70° C., and stir over night. Cool the mixture to room temperature and pour onto saturated aqueous NaHCO3 (50 mL). Extract with ethyl acetate (2×), combine the organic extracts and dry (Na2SO4), filter and concentrate. Purify the crude residue by silica gel chromatography eluting with 0-20% ethyl acetate in hexanes to afford (3S)-3-[1-(6-methoxy-2-methyl-3-pyridyloxy)-3-methyl-butyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (S-2) (101 mg, 13%). The deprotection and the L-tartarte formation are performed essentially as in EXAMPLE 1 to afford the title compound. MS (m/z)=279 [M+1]

Workup

  1. temperatureCool the mixture to room temperature
  2. extractionExtract with ethyl acetate (2×)
  3. dry with materialdry (Na2SO4)
  4. filtrationfilter
  5. concentrationconcentrate
  6. customPurify the crude residue by silica gel chromatography
  7. washeluting with 0-20% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-7ffece9032d547ddaf90178f809de1fd
Source dataset
uspto-grants-2012_05
Patent number
US08173821B2

Reaction notes

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