4-Bromo-1H-pyrrolo(2,3-c)pyridine → 2-Methyl-2-(4-((4-morpholino-2-(1h-pyrrolo[2,3-c]pyridin-4-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propanamide

HRID 1922877Notes

Reaction equation

HRID 1922877 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[CH:48]=[N:47][CH:46]=[C:45]2[NH:49][CH:50]=[CH:51][C:44]=12>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:40][C:36]([N:33]1[CH2:32][CH2:31][N:30]([CH2:29][C:27]2[S:28][C:8]3[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[N:12][C:11]([C:43]4[CH:48]=[N:47][CH:46]=[C:45]5[NH:49][CH:50]=[CH:51][C:44]=45)=[N:10][C:9]=3[CH:26]=2)[CH2:35][CH2:34]1)([CH3:41])[C:37]([NH2:39])=[O:38]

Participants

6

Reactant 2

HCID 125100554-Bromo-1H-pyrrolo(2,3-c)pyridineHCID 575067302-[4-(4-Morpholin-4-yl-2-(tributylstannanyl)-thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide

Product 1

HCID 498340392-Methyl-2-(4-((4-morpholino-2-(1h-pyrrolo[2,3-c]pyridin-4-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propanamideYield 39%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
140 °C

Procedure

A mixture of 2-[4-(4-morpholin-4-yl-2-(tributlystannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (1.17 g, 1.69 mmol), 4-bromo-1H-pyrrolo[2,3-c]pyridine (432 mg, 2.19 mmol), tetrakis(triphenylphosphine)palladium (194 mg, 10 mol %) and CuI (385 mg, 2.02 mmol) in dioxane (20 mL) was purged with argon gas then heated at 140° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM then eluted with 2 M NH3 in MeOH/DCM. The resulting residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 20:80). The resulting solid was dissolved in MeOH, loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to afford 105 as a pale yellow solid (242 mg, 39%). LCMS (Method F): RT 4.51 min, [M+H]+ 521.2. 1H NMR (DMSO, 400 MHz): δ 11.75 (s, 1H); 9.13 (s, 1 H); 8.81 (s, 1 H); 7.71 (t, J=2.7 Hz, 1 H); 7.45 (s, 1 H); 7.40-7.37 (m, 1 H); 7.07 (d, J=3.5 Hz, 1 H); 6.95 (d, J=3.5 Hz, 1 H); 4.01 (t, J=4.6 Hz, 4 H); 3.87 (s, 2 H); 3.83 (t, J=4.6 Hz, 4 H); 2.58 (s, 4 H); 2.49 (s, 4 H); 1.10 (s, 6 H)

Workup

  1. customwas purged with argon gas
  2. washwashed with MeOH/DCM
  3. washthen eluted with 2 M NH3 in MeOH/DCM
  4. customThe resulting residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 20:80)
  5. dissolutionThe resulting solid was dissolved in MeOH
  6. washwashed with MeOH
  7. washthen eluted with 2 M NH3 in MeOH

Sources & evidence

ORD record
ord-a71822e5ef004ec890e65c22b5d27c02
Source dataset
uspto-grants-2012_05
Patent number
US08173650B2

Reaction notes

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