Hydrochloric Acid → HCID 68807523, compound

HRID 411280Notes

Reaction equation

HRID 411280 reaction equation
[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH:15]([CH3:17])[CH3:16])[CH:9]=2)[C@H:4]([CH3:18])[CH2:3]1.[CH2:19]([Li])[CH2:20][CH2:21]C.Cl.C1C[O:28]CC1>>[CH3:16][CH:15]([O:14][C:10]1[CH:9]=[C:8]([C@@:5]23[CH2:6][C@H:7]([CH2:19][C:20](=[O:28])[CH2:21]2)[N:2]([CH3:1])[CH2:3][C@H:4]3[CH3:18])[CH:13]=[CH:12][CH:11]=1)[CH3:17]

Participants

5

Reactant 4

HCID 313Hydrochloric AcidHCID 8028Tetrahydrofuran2×HCID 68804566HCID 68804566, compoundHCID 178418339Butyllithium

Product 1

HCID 68807523HCID 68807523, compoundYield 70%

Conditions

Temperature
-10 °C

Procedure

To a solution of (S)-1,2,3,6-tetrahydro-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]pyridine (14) (1 eq) dissolved in THF (20 mL/g) and cooled to −10° C. was added n-butyl lithium (1.6M in hexanes) slowly until a red color is maintained followed by an addition of 1.1 eq. This material is stirred for 1 h at 10° C. and then cannulated quickly into a solution of Okahara's reagent (distilled to high purity) in THF (15 mL/g, 1.1 eq) at −78° C. followed by stirring for 2 h. The temperature should be kept below −30° C. during cannulation. This material is then poured into 2N HCl and extracted twice with ethyl ether. The aqueous layer is allowed to stand for 15 min followed by addition of 50% NAOH to pH 14 and extraction (3×) with ethyl ether. The ether is then washed (1N NaOH, H2O) and the solvent removed under vacuum. The resulting residue of product and water is dissolved in MeOH (30 mL/g) and nitrogen is bubbled through the solution for 5 min. To this is added concentrated HCl (2 mL/g), and the mixture is allowed to stand at room temperature until the reaction is complete as indicated by TLC (TLC condition: SiO2; elution with 50% (80% CHCl3:18% CH3OH:2% NH4OH) in CHCl3. Detection: 5% phosphomolybdic acid in ethanol. To this mixture was added 50% NaOH to adjust the pH to ˜10 and the methanol is removed under aspirator vacuum. The aqueous residue is then extracted several times with 3:1 (methylene chloride:THF). The organic extracts are combined and washed twice with water and once with brine, dried over sodium sulfate and evaporated to an oil. This material was purified by flash chromatography on silica gel using 25-50% (80% CHCl3:18% CH3OH:2% NH4OH) in CHCl3 to give 15 in 70% yield from 14. 1H NMR 7.24 (t,1,J=7.5 Hz), 6.77 (m, 3), 4.55 (m, 1), 3.49 (s, 1), 2.91 (dd,2,J=17 Hz and 16.5 Hz), 2.60 (m, 2), 2.35 (m, 5), 2.05 (m, 3), 1.35 (m, 6), 0.78 (d,3,J=6.8 Hz).

Workup

  1. temperatureis maintained
  2. additionfollowed by an addition of 1.1 eq
  3. stirringby stirring for 2 h
  4. customshould be kept below −30° C. during cannulation
  5. extractionextracted twice with ethyl ether
  6. waitto stand for 15 min
  7. additionfollowed by addition of 50% NAOH to pH 14 and extraction (3×) with ethyl ether
  8. washThe ether is then washed (1N NaOH, H2O)
  9. customthe solvent removed under vacuum
  10. dissolutionThe resulting residue of product and water is dissolved in MeOH (30 mL/g)
  11. customnitrogen is bubbled through the solution for 5 min
  12. additionTo this is added concentrated HCl (2 mL/g)
  13. customto stand at room temperature until the reaction
  14. washelution with 50% (80% CHCl3:18% CH3OH:2% NH4OH) in CHCl3
  15. additionTo this mixture was added 50% NaOH
  16. customthe methanol is removed under aspirator vacuum
  17. extractionThe aqueous residue is then extracted several times with 3:1 (methylene chloride:THF)
  18. washwashed twice with water and once with brine
  19. dry with materialdried over sodium sulfate
  20. customevaporated to an oil
  21. customThis material was purified by flash chromatography on silica gel using 25-50% (80% CHCl3:18% CH3OH:2% NH4OH) in CHCl3

Sources & evidence

ORD record
ord-8c463e452ade4d02b0532040b24e41a9
Source dataset
uspto-grants-2003_05
Patent number
US06559159B2

Reaction notes

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