3-bromo-5-[[1-(tert-butoxycarbonyl)-2(R)-pyrrolidinyl]methoxy]pyridine → 3-[[1-(tert-Butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-[4-[2-(4-fluorobenzyloxy)ethyl]-1-piperidinyl]pyridine

HRID 2095448Notes

Reaction equation

HRID 2095448 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.[F:22][C:23]1[CH:38]=[CH:37][C:26]([CH2:27][O:28][CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:25][CH:24]=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:34]2[CH2:35][CH2:36][CH:31]([CH2:30][CH2:29][O:28][CH2:27][C:26]3[CH:37]=[CH:38][C:23]([F:22])=[CH:24][CH:25]=3)[CH2:32][CH2:33]2)[CH:7]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]

Participants

7

Reactant 3

HCID 154802363-bromo-5-[[1-(tert-butoxycarbonyl)-2(R)-pyrrolidinyl]methoxy]pyridineHCID 207353244-[2-(4-Fluorobenzyloxy)ethyl]piperidineHCID 23676156Sodium t-butoxide

Product 1

HCID 593717483-[[1-(tert-Butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-[4-[2-(4-fluorobenzyloxy)ethyl]-1-piperidinyl]pyridineYield 80.2%

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(R)-pyrrolidinyl]methoxy]pyridine (264 mg, 0.74 mmol) and 4-[2-(4-fluorobenzyloxy)ethyl]piperidine (193 mg, 0.81 mmol, 1.1 equiv.) in anhydrous toluene (4 mL) were added successively sodium tert-butoxide (106 mg, 1.11 mmol, 1.5 equiv.), tris(dibenzylideneacetone)dipalladium(0) (13.5 mg, 15 μmol, 0.02 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 25.6 mg, 44 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 4:1, then 1:1. 3-[[1-(tert-Butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-[4-[2-(4-fluorobenzyloxy)ethyl]-1-piperidinyl]pyridine (305 mg, 80%) was obtained as a pale yellow oil.

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 4:1

Sources & evidence

ORD record
ord-09e0baea4cfe4d45a1cf66ae8de96046
Source dataset
uspto-grants-2013_05
Patent number
US08445684B2

Reaction notes

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