1,2-Dimethoxyethane → 5-Propynyl-3-(1-methyl-2-pyrrolidinyl)pyridine

HRID 1489404

Reaction equation

HRID 1489404 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH3:13])[CH:5]=[N:6][CH:7]=1.[C:14]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:19]=CC=C[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>[Pd].[Cu]I.O>[C:15]([C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH3:13])[CH:5]=[N:6][CH:7]=1)#[C:14][CH3:19]

Participants

8

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 11430Potassium CarbonateHCID 11776TriphenylphosphineHCID 110320273-Bromo-5-(1-methyl-pyrrolidin-2-yl)-pyridine

Product 1

HCID 196943595-Propynyl-3-(1-methyl-2-pyrrolidinyl)pyridineYield 312.1%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 962WaterSolvent

Conditions

Temperature
90 °C

Procedure

A Parr hydrogenation vessel was charged with 5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine (1 g, 4.15 mmol), 10% palladium on charcoal (106 mg, 0.1 mmol), copper(I)iodide (38 mg, 0.2 mmol), triphenylphosphine (104 mg, 0.4 mmol) and potassium carbonate (1.38 g, 10 mmol), DME (10 mL) and water (10 mL). The vessel was evacuated and propyne gas was introduced to a pressure of 20 p.s.i. The mixture was agitated and heated at 90° C. for 6 days, readmitting propyne gas as necessary. Analysis by GC at this stage indicated about 40% completion and the cooled mixture was filtered through celite and the filtrate concentrated in vacuo. The mixture was then acidified with 1M HCl (50 mL) and extracted with toluene (50 mL). The aqueous layer was made basic with solid potassium carbonate and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate extracts were washed with water (50 mL), dried (MgSO4) and concentrated to afford an oil. The crude product was purified by silica gel column chromatography with ethyl acetate:hexane (1:1) as eluant to afford 5-propynyl-3-(1-methyl-2-pyrrolidinyl)pyridine (250 mg, 30%). A portion (225 mg) of this material was converted to the title compound by the addition of one equivalent of fumaric acid to a methanol (10 mL) solution of the free amine at 25° C. After 30 minutes the solvent was removed in vacuo and the residue pumped under high vacuum. Trituration with diethyl ether followed by recrystallization from ethyl acetate afforded 5-[1-(1-propynyl)]-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate, 180 mg, 50%. M.p. 188°-189° C. (EtOAc); 1H NMR (DMSO-d6, 300 MHz): δ 8.49 (s, 1H), 8.47 (s, 1H), 7.77 (s, 1H), 6.60 (s, 2H), 3.34 (t, J=9 Hz, 1H), 3.25 (app. t, J=9 Hz, 1H), 2.41 (dd, J=9, 9 Hz, 1H), 2.22 (m, 1H), 2.16 (s, 3H), 2.08 (s, 3H), 1.85 (m, 2H), 1.69 (m, 1H).

Workup

  1. customThe vessel was evacuated
  2. additionpropyne gas was introduced to a pressure of 20 p.s.i
  3. filtrationAnalysis by GC at this stage indicated about 40% completion and the cooled mixture was filtered through celite
  4. concentrationthe filtrate concentrated in vacuo
  5. extractionextracted with toluene (50 mL)
  6. extractionextracted with ethyl acetate (2×100 mL)
  7. washThe combined ethyl acetate extracts were washed with water (50 mL)
  8. dry with materialdried (MgSO4)
  9. concentrationconcentrated
  10. customto afford an oil
  11. customThe crude product was purified by silica gel column chromatography with ethyl acetate:hexane (1:1) as eluant

Sources & evidence

ORD record
ord-62c675aaab644af987824c82cad6d7cf
Source dataset
uspto-grants-1997_10
Patent number
US05677459

Linked notes

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