3,5-Dichloropyridine → HCID 118383571, compound

HRID 2202707Notes

Reaction equation

HRID 2202707 reaction equation
[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.[CH:37]([CH:40]1[CH2:49][N:43]2S(=O)(=O)O[CH2:46][C@H:42]2[CH2:41]1)([CH3:39])[CH3:38]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH2:46][C@H:42]1[CH2:41][CH:40]([CH:37]([CH3:39])[CH3:38])[CH2:49][NH:43]1

Participants

6

Reactant 4

HCID 171533,5-DichloropyridineHCID 2724682Lithium diisopropylamideHCID 22742125Tetrahydrofuran heptane ethylbenzolHCID 118383050HCID 118383050, compound

Product 1

HCID 118383571HCID 118383571, compoundYield 36.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 3,5-dichloropyridine (228 mg, 1.542 mmol) in THF (2.6 mL) at −78° C. was added lithium diisopropylamide, 2.0 M heptane/THF/ethylbenzene (0.976 mL, 1.953 mmol) dropwise. After stirring for 45 min, a solution of (3aR)-5-isopropyltetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (211 mg, 1.028 mmol) in THF (3.0 mL) was added dropwise at −78° C. The resulting mixture was allowed to warm to room temperature and then stirred for 3 h. After evaporation of the solvent, the resulting brown solid was treated with 2 N HCl (3 mL) and EtOH (3 mL) and heated at 80° C. for 2 h. The reaction mixture was concentrated to remove the EtOH. The resulting mixture was treated with ice and basified with 2 N NaOH to pH-10 and extracted with EtOAc (2×10 mL). The extracts were dried, evaporated and purified by ISCO, chromatograph through a REDISEP™ pre-packed silica gel column (12 g), eluting with a gradient of 0% to 5% MeOH (with 2 M NH3) in DCM to give 3,5-dichloro-4-(((2R)-4-isopropylpyrrolidin-2-yl)methyl)pyridine (102 mg, 0.373 mmol, 36.3% yield) as an orange oil. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 2H), 3.35-3.51 (m, 1H), 2.84-3.08 (m, 3H), 2.35-2.44 (m, 1H), 1.80-1.93 (m, 1H), 1.55-1.69 (m, 1H), 1.31-1.49 (m, 2H), 1.02-1.17 (m, 1H), 0.85 (t, J=6.7 Hz, 6H).

Workup

  1. stirringstirred for 3 h
  2. customAfter evaporation of the solvent
  3. additionthe resulting brown solid was treated with 2 N HCl (3 mL) and EtOH (3 mL)
  4. temperatureheated at 80° C. for 2 h
  5. concentrationThe reaction mixture was concentrated
  6. customto remove the EtOH
  7. additionThe resulting mixture was treated with ice and basified with 2 N NaOH to pH-10
  8. extractionextracted with EtOAc (2×10 mL)
  9. customThe extracts were dried
  10. customevaporated
  11. custompurified by ISCO, chromatograph through a REDISEP™ pre-packed silica gel column (12 g)
  12. washeluting with a gradient of 0% to 5% MeOH (with 2 M NH3) in DCM

Sources & evidence

ORD record
ord-b9206a61bd214f1dad295538c39cf0e3
Source dataset
uspto-grants-2016_06
Patent number
US09365522B2

Reaction notes

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