Nitrogen → N,N-dimethyl-3-(6-methyl-5-nitropyridin-3-yl)prop-2-yn-1-amine

HRID 2388006Notes

Reaction equation

HRID 2388006 reaction equation
N#N.Br[C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[C:7]([CH3:10])=[N:8][CH:9]=1.CCN(CC)CC.[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[CH:25]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[C:25][C:4]1[CH:9]=[N:8][C:7]([CH3:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1

Participants

8

Reactant 4

HCID 947NitrogenHCID 8471TriethylamineHCID 81643N,N-DimethylpropargylamineHCID 250672665-Bromo-2-methyl-3-nitropyridine

Product 1

HCID 58476572N,N-dimethyl-3-(6-methyl-5-nitropyridin-3-yl)prop-2-yn-1-amine

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

A 12 L reactor equipped with an overhead stirrer and N2 bubbler was charged with a solution of 5-bromo-2-methyl-3-nitropyridine (945 g, 4.35 mol) in EtOAc (5.7 L, 6 vol). To the reaction mixture, Pd(PPh3)2Cl2 (15.4 g, 0.022 mol, 0.005 equiv), CuI (8.28 g, 0.0435 mol, 0.01 equiv) and Et3N (3 L, 21.75 mol, 5 equiv) were added. Nitrogen was bubbled through the solution for 15 min and 3-dimethylamino-1-propyne (556 mL, 5.22 mol, 1.2 equiv) was added. The reaction-temperature setting was increased to 60° C. stepwise. The maximum temperature attained was 66° C. The reaction was continued for 3 h at this temperature (60° C.) and was judged complete by HPLC analysis. The reaction was cooled to ambient temperature and the inorganic salts were filtered off by passing the reaction mixture through a pad of celite. The filter cake was washed with EtOAc (2 L, 2 vol). The filtrate was transferred into a 20 L separatory funnel. The EtOAc layer was washed with 5% aqueous Na2CO3 solution (2×5 L, 5 vol). The layers were separated. The EtOAc layer was then washed with 10% brine in water (5 L, 5 vol). The layers were separated and the EtOAc layer was pumped down to a low volume (ca. 2 L, 2 vol) under reduced pressure. IPA (5 L, 5 vol) was added to the solution and the solvent was again evaporated to a low volume (ca. 2 L, 2 vol). The solution of N,N-dimethyl-3-(6-methyl-5-nitropyridin-3-yl)prop-2-yn-1-amine was subjected to hydrogenation in two batches using the procedure described in step 2, below.

Workup

  1. customA 12 L reactor equipped with an overhead stirrer
  2. customNitrogen was bubbled through the solution for 15 min
  3. customattained was 66° C
  4. temperatureThe reaction was cooled to ambient temperature
  5. filtrationthe inorganic salts were filtered off
  6. washThe filter cake was washed with EtOAc (2 L, 2 vol)
  7. customThe filtrate was transferred into a 20 L separatory funnel
  8. washThe EtOAc layer was washed with 5% aqueous Na2CO3 solution (2×5 L, 5 vol)
  9. customThe layers were separated
  10. washThe EtOAc layer was then washed with 10% brine in water (5 L, 5 vol)
  11. customThe layers were separated
  12. additionIPA (5 L, 5 vol) was added to the solution
  13. customthe solvent was again evaporated to a low volume (ca. 2 L, 2 vol)

Sources & evidence

ORD record
ord-4e4bf9a9fca041f3bf4716927f6cc369
Source dataset
uspto-grants-2012_09
Patent number
US08268992B2

Reaction notes

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