Triethylamine → HCID 66710459, compound

HRID 1631835Notes

Reaction equation

HRID 1631835 reaction equation
[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.Cl.[C:13]([C:15]1[CH:28]=[CH:27][C:18]([CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:17][CH:16]=1)#[N:14].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:26][CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:18]3[CH:27]=[CH:28][C:15]([C:13]#[N:14])=[CH:16][CH:17]=3)[CH2:21][CH2:22]2)=[O:10])=[N:6][CH:7]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 6085445-Bromopyridine-2-carboxylic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 44120478HCID 44120478, compound

Product 1

HCID 66710459HCID 66710459, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 5-bromopicolinic acid (0.50 g, 2.48 mmol, 1.0 eq) and 1-(4-cyanobenzyl)-4-aminopiperidine dihydrochloride (0.71 g, 2.48 mmol, 1.0 eq) in dimethylformamide (10 mL) was added triethylamine (1.21 mL, 8.66 mmol, 3.5 eq) and HATU (1.13 g, 2.97 mmol, 1.2 eq). The reaction mixture was stirred at room temperature 14 hours before partitioning between EtOAc (120 mL) and water (100 mL). The organics were washed with brine (100 mL), water (100 mL) and brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (0%, 5%, 10% MeOH—CH2Cl2, 0→5→25→35 min) yielded 5-bromo-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide as a waxy brown solid: 1H nmr (CDCl3) 8.60 (1H, d, J 2.0 Hz, pyH-6), 8.07 (1H, d, J 8.5 Hz, pyH-3), 7.97 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.84 (1H, d, J 7.5 Hz, NH), 7.63 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.50 (2H, d, J 8.0 Hz, 2H of C6H4CN), 4.00 (1H, m, pipH-4), 3.63 (2H, s, CH2C6H4CN), 2.88 (2H, m, 2H of pip), 2.30 (2H, m, 2H of pip), 2.04 (2H, m, 2H of pip), 1.70 (2H, m, 2H of pip); m/z 399, 401 [M+H]+. To a mixture of the 5-bromo-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide (0.040 g, 0.100 mmol, 1.0 eq) 4-(4-piperidinyloxy)benzonitrile (0.024 g, 0.120 mmol, 1.2 eq), sodium t-butoxide (0.019 g, 0.201 mmol, 2.0 eq) and S-Phos (0.004 g, 0.010 mmol, 0.1 eq) was added toluene (1.0 mL). The resulting mixture was degassed by bubbling argon through the mixture. Tris(dibenzylideneacetone)dipalladium (0.005 g, 0.005 mmol, 0.05 eq) was added and the mixture further degassed before sealing the reaction and heating to 105° C. for 14 hours. The reaction was filtered through celite, eluting with 5% MeOH—CH2Cl2 (3×15 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by RP-HPLC to yield Compound 165: 1H nmr (CDCl3) δ 8.19 (1H, d, J 3.0 Hz, pyH-6), 8.04 (1H, d, J 9.0 Hz, pyH-3), 7.72 (1H, d, J 8.5 Hz, NH), 7.60 (4H, m, 2H of OC6H4CN, 2H of CH2C6H4CN), 7.45 (2H, d, J 8.0 Hz, 2H of CH2C6H4CN), 7.24 (1H, dd, J 8.0, 3.0 Hz, pyH-4), 6.97 (2H, d, J 9.0 Hz, 2H of OC6H4CN), 4.64 (1H, m, PhOpipH-4), 3.98 (1H, m, pipH-4), 3.63-3.57 (2H, m, 2H of PhOpipH-2, H-6), 3.55 (2H, s, CH2C6H4CN), 3.38-3.30 (2H, m, 2H of PhOpipH-2, H-6), 2.80 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.16-2.05 (2H, m, 2H of PhOpipH-3, H-5), 2.01-1.92 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5); m/z: 522 [M+H]+.

Workup

  1. custombefore partitioning between EtOAc (120 mL) and water (100 mL)
  2. washThe organics were washed with brine (100 mL), water (100 mL) and brine (100 mL)
  3. dry with materialdried (Na2SO4)
  4. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-687440385fd643de827a4ef84601fca6
Source dataset
uspto-grants-2014_07
Patent number
US08791136B2

Reaction notes

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