3,5-Dichloropyridine → HCID 118383348, compound

HRID 2202765Notes

Reaction equation

HRID 2202765 reaction equation
C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=1.[CH:17]1([C@H:23]2[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([CH:35]=[O:36])[CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.N1CCCC1>C1COCC1>[CH:17]1([C@H:23]2[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C@H:25]([C@H:35]([C:15]3[C:14]([Cl:16])=[CH:13][N:12]=[CH:11][C:10]=3[Cl:9])[OH:36])[CH2:24]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1

Participants

6

Reactant 4

HCID 171533,5-DichloropyridineHCID 31268PyrrolidineHCID 2724682Lithium diisopropylamideHCID 118382885HCID 118382885, compound

Product 1

HCID 118383348HCID 118383348, compoundYield 76%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

Lithium diisopropylamide (2.0 M solution in heptane/THF/ethylbenzene, 3.51 mL, 7.02 mmol) was added to 3,5-dichloropyridine (820 mg, 5.54 mmol) dissolved in THF (15 mL) cooled at −78° C. and stirred at this temperature for 1 h. (2S,4S)-tert-butyl 4-cyclohexyl-2-formylpyrrolidine-1-carboxylate (1.04 g, 3.70 mmol) and its epimer at C2 of the pyrrolidine in THF (11 mL) was added and the solution was removed from the cooling bath and allowed to warm to room temperature and stirred for 2 h. The solution was quenched with saturated ammonium chloride, the aqueous layer was extracted with EtOAc (2×50 mL) and the organic layer washed with brine (30 mL) and dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified on an ISCO Combiflash™ RF (40 g Grace Reverlis column, using a gradient of 0-80% EtOAc in heptane) affording (2S,4S)-tert-butyl 4-cyclohexyl-2-((S)-(3,5-dichloropyridin-4-yl)(hydroxy)methyl)pyrrolidine-1-carboxylate (1.20 g, 2.79 mmol, 76% yield) as a mixture of epimers. MS (ESI) 451.1, 453.1 [M+Na]+.

Workup

  1. additionwas added
  2. customthe solution was removed from the cooling bath
  3. temperatureto warm to room temperature
  4. customThe solution was quenched with saturated ammonium chloride
  5. extractionthe aqueous layer was extracted with EtOAc (2×50 mL)
  6. washthe organic layer washed with brine (30 mL)
  7. dry with materialdried over anhydrous magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe crude product was purified on an ISCO Combiflash™ RF (40 g Grace Reverlis column

Sources & evidence

ORD record
ord-52232ddbe95141fba00a324e4dfdb0eb
Source dataset
uspto-grants-2016_06
Patent number
US09365522B2

Reaction notes

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