Diisopropylethylamine → 3-(Chloromethyl)pyridine

HRID 1782571Notes

Reaction equation

HRID 1782571 reaction equation
[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C@H:17]([CH3:21])[CH2:18][C:19]#[N:20])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1)[CH3:2].Cl.[C:23]([Cl:31])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:19]([CH2:18][C@H:17]([N:14]1[CH2:15][CH2:16][CH:11]([N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=2)[CH2:12][CH2:13]1)[CH3:21])#[N:20].[CH2:23]([Cl:31])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 884383-Pyridinecarbonyl chloride, hydrochloride (1:1)HCID 68971325(R)-3-[4-(4-ethoxy-phenylamino)-piperidin-1-yl]-butyronitrile

Product 2

HCID 183583-(Chloromethyl)pyridineYield 88%HCID 68971112n-[(r)-1-(2-Cyano-1-methyl-ethyl)-piperidin-4-yl]-n-(4-ethoxy-phenyl)-nicotinamide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
80 °C

Procedure

A solution of the above nitrile (0.18 g, 0.63 mmol) and nicotinoyl chloride hydrochloride (0.45 g, 2.5 mmol) in THF (6 mL) was then treated with DIPEA (0.55 mL, 3.2 mmol) and stirred at 80° C. for 16 h. The reaction was cooled to room temperature, concentrated under reduced pressure, diluted with CH2Cl2 (10 mL) and washed with brine solution (2×10 mL). The combined organic extracts were then dried (Na2SO4), filtered and concentrated and the crude material purified by flash column chromatography on silica gel (25:1:0.1 CH2Cl2/MeOH/NH4OH) to afford N-[(R)-1-(2-cyano-1-methyl-ethyl)-piperidin-4-yl]-N-(4-ethoxy-phenyl)-nicotinamide impure with nicotinyl chloride (88%).

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. concentrationconcentrated under reduced pressure
  3. additiondiluted with CH2Cl2 (10 mL)
  4. washwashed with brine solution (2×10 mL)
  5. dry with materialThe combined organic extracts were then dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customthe crude material purified by flash column chromatography on silica gel (25:1:0.1 CH2Cl2/MeOH/NH4OH)

Sources & evidence

ORD record
ord-b222b2d037df440cacc60dbb104c5f4c
Source dataset
uspto-grants-2009_03
Patent number
US07498346B2

Reaction notes

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