4-Methylmorpholine → N-methoxy-N-methyl-2-amino-5-bromonicotinamide hydrochloride

HRID 729854Notes

Reaction equation

HRID 729854 reaction equation
[ClH:1].[CH3:2][NH:3][O:4][CH3:5].[NH2:6][C:7]1[N:15]=[CH:14][C:13]([Br:16])=[CH:12][C:8]=1[C:9](O)=[O:10].CN1CCOCC1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[ClH:1].[CH3:5][O:4][N:3]([CH3:2])[C:9](=[O:10])[C:8]1[CH:12]=[C:13]([Br:16])[CH:14]=[N:15][C:7]=1[NH2:6]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 7374452-Amino-5-bromonicotinic acidHCID 2724699PyBOP

Product 1

HCID 86602997N-methoxy-N-methyl-2-amino-5-bromonicotinamide hydrochlorideYield 74%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

In a nitrogen flushed flask 3.00 g (30.76 mmol) of N,O-dimetylhydroxylamine hydrochloride and 3.53 g (16.27 mmol) of 2-amino-5-bromonicotinic acid are dissolved in a mixture of 350 ml of dichloromethane, and 30 ml of N-methylmorpholine. 12.70 g (24.40 mmol) of PyBOP (1-benzotriazolyloxy-tris(pyrrolidino)phosphonium hexafluorophosphate) is added and the reaction mixture stirred at room temperature for 5 hours. The mixture is then washed with 150 ml of a 2 M solution of sodium hydroxide in water and then twice with 100 ml of a 10% aqueous citric acid solution and dried over sodium sulfate. The solvent is evaporated and the resulting oil is dissolved in 300 ml of ether. The precipitate formed is filtered off and discarded. The clear filtrate is concentrated to about half its volume and diluted with 30-60 ml of dichloromethane. The resulting solution is stirred vigorously and a 1 M solution of hydrogen chloride in anhydrous ether is added until formation of the resulting precipitate is complete. The precipitate is filtered off, washed with ether and dried by suction to afford 3.15 g (12.04 mmol, 74% yield) of N-methoxy-N-methyl-2-amino-5-bromonicotinamide hydrochloride as an off-white to beige-brown powder. 1H-NMR (d6-DMSO) δ: 8.24 [1H] d, 7.97 [1H] d, 3.56 [3H] s, 3.26 [3H] s. MS: m/z 260 [MH+]

Workup

  1. washThe mixture is then washed with 150 ml of a 2 M solution of sodium hydroxide in water
  2. dry with materialtwice with 100 ml of a 10% aqueous citric acid solution and dried over sodium sulfate
  3. customThe solvent is evaporated
  4. dissolutionthe resulting oil is dissolved in 300 ml of ether
  5. customThe precipitate formed
  6. filtrationis filtered off
  7. concentrationThe clear filtrate is concentrated to about half its volume
  8. additiondiluted with 30-60 ml of dichloromethane
  9. stirringThe resulting solution is stirred vigorously
  10. additiona 1 M solution of hydrogen chloride in anhydrous ether is added until formation of the resulting precipitate
  11. filtrationThe precipitate is filtered off
  12. washwashed with ether
  13. customdried by suction

Sources & evidence

ORD record
ord-6e0ec4c0ee2b4e42908ab86baf63d7cb
Source dataset
uspto-grants-2009_09
Patent number
US07582637B2

Reaction notes

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