Trifluoroacetic acid → N-(2-aminophenyl)-4-(3-cyano-5-{[(tetrahydro-2h-pyran-4-ylmethyl)amino]methyl}pyridin-2-yl)benzamide

HRID 599516Notes

Reaction equation

HRID 599516 reaction equation
C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:33])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[CH:27][C:26]([CH:31]=O)=[CH:25][N:24]=2)=[CH:19][CH:18]=1)=O)(C)(C)C.[NH2:34][CH2:35][CH:36]1[CH:41]=[CH:40]N[CH2:38][CH2:37]1.[BH4-].[Na+].C(=O)(O)[O-:45].[Na+].FC(F)(F)C(O)=O>ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O.CO>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:33])[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:28]([C:29]#[N:30])=[CH:27][C:26]([CH2:31][NH:34][CH2:35][CH:36]3[CH2:41][CH2:40][O:45][CH2:38][CH2:37]3)=[CH:25][N:24]=2)=[CH:21][CH:22]=1

Participants

10

Reactant 5

HCID 6422Trifluoroacetic acidHCID 516892Sodium BicarbonateHCID 4311764Sodium borohydrideHCID 672699494-AminomethyltetrahydropyridineHCID 86624985HCID 86624985, compound

Product 1

HCID 11517839N-(2-aminophenyl)-4-(3-cyano-5-{[(tetrahydro-2h-pyran-4-ylmethyl)amino]methyl}pyridin-2-yl)benzamide

Reagents, catalysts & solvents 4

HCID 11026Titanium isopropoxideCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Procedure

N-(2-t-Butoxycarbonylaminophenyl)-4-(3-cyano-5-formylpyridin-2-yl)benzamide (0.20 g, 0.45 mmol; prepared as described in Method 15 below) and 4-aminomethyltetrahydropyridine (81 mg, 0.7 mmol) were dissolved in dichloromethane (6 ml). Titanium (IV) isopropoxide (0.27 ml, 0.9 mmol) was added and the mixture stirred at ambient temperature for 2 hours. Sodium borohydride (70 mg) and methanol (0.6 ml) were then added and the mixture stirred for a further 16 hours. Water (4 ml) and a saturated aqueous sodium bicarbonate solution (2 ml) were added and stirred for 10 minutes. The product was extracted with dichloromethane (3×10 ml) and the organic residues concentrated. The residue was purified using chromatography eluting with 10% methanol in ethyl acetate, and concentration of the solvent gave product as a gum. This was dissolved in dichloromethane (6 ml), trifluoroacetic acid (1.2 ml) added and the solution then stirred at ambient temperature for 2 hours. The resulting solution was absorbed onto an SCX-2 column, which was washed with methanol (3 column volumes) and then the product eluted with a 2M solution of ammonia in methanol (3 column volumes) then concentrated to give the product as a gum. This was re-precipitated by stirring in diethyl ether (3 ml) to give the title compound as a foam (73 mg, 37%). NMR Spectrum: (DMSO-d6) 1.18 (m, 2H), 1.66 (m, 3H), 2.46 (d, 2H), 3.29 (m, 2H), 3.85 (m, 4H), 4.95 (s, 2H), 6.62 (m, 1H), 6.80 (d, 1H), 7.00 (m, 1H), 7.21 (d, 1H), 8.00 (d, 2H), 8.16 (d, 2H), 8.39 (s, 1H), 8.39 (s, 1H), 9.78 (s, 1H); Mass Spectrum: M+H+ 442.

Workup

  1. stirringthe mixture stirred for a further 16 hours
  2. stirringstirred for 10 minutes
  3. extractionThe product was extracted with dichloromethane (3×10 ml)
  4. concentrationthe organic residues concentrated
  5. customThe residue was purified
  6. washeluting with 10% methanol in ethyl acetate, and concentration of the solvent
  7. customgave product as a gum
  8. stirringthe solution then stirred at ambient temperature for 2 hours
  9. customThe resulting solution was absorbed onto an SCX-2 column, which
  10. washwas washed with methanol (3 column volumes)
  11. washthe product eluted with a 2M solution of ammonia in methanol (3 column volumes)
  12. concentrationthen concentrated

Sources & evidence

ORD record
ord-191f5b8a7ccd4555b88e9c5eba32b597
Source dataset
uspto-grants-2011_03
Patent number
US07897778B2

Reaction notes

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