5-Bromo-(1,2,4)triazolo(4,3-a)pyridine → 2-(4-((2-([1,2,4]Triazolo[4,3-a]pyridin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide

HRID 1923302Notes

Reaction equation

HRID 1923302 reaction equation
[N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[N:48]2[CH:49]=[N:50][N:51]=[C:47]2[CH:46]=[CH:45][CH:44]=1>O1CCOCC1.[Cu]I>[N:51]1[N:50]=[CH:49][N:48]2[C:43]([C:11]3[N:12]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[C:8]4[S:28][C:27]([CH2:29][N:30]5[CH2:31][CH2:32][N:33]([C:36]([CH3:40])([CH3:41])[C:37]([NH2:39])=[O:38])[CH2:34][CH2:35]5)=[CH:26][C:9]=4[N:10]=3)=[CH:44][CH:45]=[CH:46][C:47]=12

Participants

5

Reactant 2

HCID 441183095-Bromo-(1,2,4)triazolo(4,3-a)pyridineHCID 575067302-[4-(4-Morpholin-4-yl-2-(tributylstannanyl)-thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide

Product 1

HCID 596061272-(4-((2-([1,2,4]Triazolo[4,3-a]pyridin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamideYield 12.2%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
150 °C

Procedure

A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (150 mg, 0.22 mmol), 5-bromo-[1,2,4]triazolo[4,3-a]pyridine (51 mg, 0.26 mmol), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium (II) (15 mg, 0.02 mmol) and copper(I) iodide (41 mg, 0.22 mmol) in dioxane (2.5 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH then the desired product was eluted with 2 M NH3 in MeOH. The appropriate fractions were combined and evaporated. The resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 690 as a white solid (14 mg, 12%). LCMS (Method F) RT 5.50 min; [M+H]+ 522. 1H NMR (400 MHz, CHCl3-d): δ 10.53 (d, J=0.9 Hz, 1 H); 8.08 (dd, J=7.0, 0.9 Hz, 1 H); 7.93 (d, J=9.1 Hz, 1 H); 7.41 (dd, J=9.1, 7.0 Hz, 1 H); 7.38 (s, 1 H); 7.08 (d, J=5.3 Hz, 1 H); 5.20 (d, J=5.3 Hz, 1 H); 4.07 (t, J=4.8 Hz, 4 H); 3.92 (t, J=4.8 Hz, 4 H); 3.88 (s, 2 H); 2.62 (m, 8 H);1.25 (s, 6 H)

Workup

  1. customwas purged with argon gas
  2. washThe cartridge was washed with MeOH
  3. washthe desired product was eluted with 2 M NH3 in MeOH
  4. customevaporated
  5. customThe resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90)

Sources & evidence

ORD record
ord-82cfbb9d657c4ff99b47d7bf3f5cc10b
Source dataset
uspto-grants-2012_05
Patent number
US08173650B2

Reaction notes

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