(S)-2-((5-Bromopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester → HCID 59371561, compound

HRID 2095436Notes

Reaction equation

HRID 2095436 reaction equation
[C:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:11][C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([O:24][CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:23]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:34]([O:33][C:31]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[CH2:25][O:24][C:22]1[CH:21]=[N:20][CH:19]=[C:18]([N:14]2[CH2:15][CH2:16][C@@H:12]([CH2:11][O:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:13]2)[CH:23]=1)=[O:32])([CH3:37])([CH3:35])[CH3:36]

Participants

7

Reactant 3

HCID 15480235(S)-2-((5-Bromopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl esterHCID 23676156Sodium t-butoxideHCID 26192471HCID 26192471, compound

Product 1

HCID 59371561HCID 59371561, compoundYield 90.3%

Reagents, catalysts & solvents 3

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 3(R)-[(3-phenylpropoxy)methyl]pyrrolidine (220 mg, 1.00 mmol, 1.50 equiv.) and 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (240 mg, 0.67 mmol) in toluene (15 mL) were added sodium tert-butoxide (96 mg, 1.00 mmol, 1.5 equiv.), tris(dibenzylideneacetone)dipalladium(0) (12 mg, 13.4 μmol, 0.02 equiv.) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 23 mg, 40 μmol, 0.06 equiv.) under N2. The mixture was stirred for 4 h at 100° C. After concentration in vacuo, the residue was diluted with water and extracted with EtOAc. The combined organic layers were dried and concentrated under reduced pressure. The residue was applied onto a silica gel column, which was eluted with EtOAc/petroleum ether 1:1 to afford the product (300 mg, 90%) as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 7.68 (br s, 1H), 7.63 (br s, 1H), 7.37-7.19 (m, 5H), 6.43 (br s, 1H), 4.18-4.10 (m, 2H), 3.90 (br s, 1H), 3.49-3.29 (m, 9H), 3.13 (dd, 1H, J=9.0, 6.6 Hz), 2.74-2.61 (m, 3H), 2.20-2.12 (m, 1H), 2.06 (m, 2H), 1.99-1.82 (m, 5H). LC-MS (ESI) m/z 496 (M+H+).

Workup

  1. concentrationAfter concentration in vacuo
  2. additionthe residue was diluted with water
  3. extractionextracted with EtOAc
  4. customThe combined organic layers were dried
  5. concentrationconcentrated under reduced pressure
  6. washwas eluted with EtOAc/petroleum ether 1:1

Sources & evidence

ORD record
ord-f30645b987ff424cbe146238a6db1a9c
Source dataset
uspto-grants-2013_05
Patent number
US08445684B2

Reaction notes

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