Triethylamine → 2-(2-(3-((Methyl(2-(4-methylpiperazin-1-yl)ethyl)amino)methyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide

HRID 1408086Notes

Reaction equation

HRID 1408086 reaction equation
[CH3:1][N:2]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25](=[O:59])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[C:39]2[CH:44]=[C:43]([C:45](=[O:58])[NH:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([F:57])([F:56])[F:55])[CH:49]=3)[CH:42]=[CH:41][N:40]=2)[CH:20]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](OC(C)(C)C)=O)[CH2:7][CH2:6]1.ClCCl.C(O)(C(F)(F)F)=O.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[CH3:1][N:2]([CH2:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[C:25]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]2)=[CH:29][C:28]=1[C:39]1[CH:44]=[C:43]([CH:42]=[CH:41][N:40]=1)[C:45]([NH:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([F:55])([F:57])[F:56])[CH:49]=1)=[O:58])=[O:59])[CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 31297Methanesulfonyl chlorideHCID 21863450Trifluoroacetic acid methylene chlorideHCID 66586814Tert-butyl 4-(2-(methyl(3-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)-carbamoyl)benzyl)amino)ethyl)piperazine-1-carboxylate

Product 1

HCID 665868412-(2-(3-((Methyl(2-(4-methylpiperazin-1-yl)ethyl)amino)methyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamideYield 31.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

Into a 25-mL round-bottom flask, was placed 160 mg of tert-butyl 4-(2-(methyl(3-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)-carbamoyl)benzyl)amino)ethyl)piperazine-1-carboxylate Example 38 and 10 mL of 1:1 dichloromethane/TFA. After stirring for 2 hours, the solvent was evaporated. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic phase was dried and the solvent was evaporated. The residue was treated with triethylamine (78 mg, 0.77 mmol, 6.00 equiv), and dichloromethane (2 mL). This was followed by dropwise addition of a solution of methanesulfonyl chloride (21.9 mg, 0.19 mmol, 1.50 equiv) in dichloromethane (1 mL) with stirring at 0° C. The resulting solution was stirred for 4 h at 25° C. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 45 mg (28%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.31 (s, 1H), 9.55-9.59 (t, J=6.6 Hz, 1H), 8.93-8.94 (d, J=3 Hz, 1H), 8.35 (s, 1H), 8.27-8.30 (d, J=9 Hz, 1H), 8.09 (s, 1H), 7.96-7.98 (d, J=6 Hz, 1H), 7.85-7.86 (d, J=3 Hz, 1H), 7.56-7.76 (m, 7H), 7.31-7.34 (d, J=9 Hz, 1H), 4.62-4.64 (d, J=6 Hz, 2H), 4.39 (s, 2H), 3.34 (s, 4H), 3.22-3.24 (d, J=6 Hz, 6H), 2.90 (s, 5H), 2.74 (s, 3H), 2.69 (s, 4H), 1.75 (s, 4H), 1.60-1.61 (d, J=3 Hz, 2H). MS (ES, m/z): 792 [M+H]+.

Workup

  1. customInto a 25-mL round-bottom flask, was placed
  2. customthe solvent was evaporated
  3. customThe residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution
  4. customThe organic phase was dried
  5. customthe solvent was evaporated
  6. stirringwith stirring at 0° C
  7. stirringThe resulting solution was stirred for 4 h at 25° C
  8. concentrationThe resulting mixture was concentrated under vacuum
  9. customThe crude product (200 mg) was purified by reverse phase HPLC
  10. washeluting with a water/CH3CN gradient
  11. additioncontaining 0.05% TFA

Sources & evidence

ORD record
ord-5f7143d14670451785b3c30fa669c307
Source dataset
uspto-grants-2014_12
Patent number
US08916569B2

Reaction notes

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