(S)-2-((5-Bromopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester → 3-[[N-(tert-Butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-[4-[2-(4-methoxybenzyloxy)ethyl]-1-piperidinyl]pyridine

HRID 2095456Notes

Reaction equation

HRID 2095456 reaction equation
Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=1.[CH3:22][O:23][C:24]1[CH:39]=[CH:38][C:27]([CH2:28][O:29][CH2:30][CH2:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:26][CH:25]=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:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[CH2:9][O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([N:35]2[CH2:36][CH2:37][CH:32]([CH2:31][CH2:30][O:29][CH2:28][C:27]3[CH:38]=[CH:39][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[CH2:33][CH2:34]2)[CH:7]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]

Participants

7

Reactant 3

HCID 15480235(S)-2-((5-Bromopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl esterHCID 23676156Sodium t-butoxideHCID 568305684-[2-(4-Methoxybenzyloxy)ethyl]piperidine

Product 1

HCID 593716743-[[N-(tert-Butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-[4-[2-(4-methoxybenzyloxy)ethyl]-1-piperidinyl]pyridineYield 84.1%

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
99 °C

Procedure

To a solution of 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (112 mg, 0.31 mmol) and 4-[2-(4-methoxybenzyloxy)ethyl]piperidine (86 mg, 0.34 mmol, 1.1 equiv.) in anhydrous toluene (2 mL) were added successively sodium tert-butoxide (45 mg, 0.47 mmol, 1.5 equiv.), Pd2dba3 (5.7 mg, 6.0 μmol, 0.02 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 10.8 mg, 19 μmol, 0.06 equiv.). The mixture was degassed and purged with Ar (3 cycles), then warmed to 98-100° C. for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc, and the solution was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by CC on SiO2 with CH2Cl2/EtOAc 3:2, then 1:2. The product (137 mg, 84%) was obtained as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.23-7.30 (m, 3H), 7.24 (d, 2H, J=8.4 Hz), 6.86 (d, 2H, J=8.4 Hz), 4.41 (s, 2H), 4.10 (m, 2H), 3.90-3.80 (m, 1H), 3.78 (s, 3H), 3.65 (m, 2H), 3.49 (t, 2H, J=6.0 Hz), 3.39 (m, 2H), 2.72 (m, 2H), 2.02 (m, 3H), 1.84 (m, 1H), 1.75 (d, 2H, J=12.4 Hz), 1.55 (m, 3H), 1.45 (s, 9H), 1.31 (m, 2H).

Workup

  1. customThe mixture was degassed
  2. custompurged with Ar (3 cycles)
  3. temperatureAfter cooling to room temperature
  4. additionthe mixture was diluted with EtOAc
  5. washthe solution was washed with brine
  6. dry with materialdried over Na2SO4
  7. customevaporated
  8. customThe residue was purified by CC on SiO2 with CH2Cl2/EtOAc 3:2

Sources & evidence

ORD record
ord-89ef7848fffa44cc971abd2a19361f41
Source dataset
uspto-grants-2013_05
Patent number
US08445684B2

Reaction notes

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