5-Bromoimidazo(1,2-a)pyridine → 4-(1-((2-(Imidazo[1,2-a]pyridin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)morpholine

HRID 1923298Notes

Reaction equation

HRID 1923298 reaction equation
[N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][CH:33]([N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)[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]=[CH:50][N:51]=[C:47]2[CH:46]=[CH:45][CH:44]=1>C1COCC1.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>[N:51]1[CH: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[CH2:35][CH2:34][CH:33]([N:36]6[CH2:41][CH2:40][O:39][CH2:38][CH2:37]6)[CH2:32][CH2:31]5)=[CH:26][C:9]=4[N:10]=3)=[CH:44][CH:45]=[CH:46][C:47]=12

Participants

6

Reactant 2

HCID 130372415-Bromoimidazo(1,2-a)pyridineHCID 596059194-Morpholin-4-yl-6-(4-morpholin-4-ylpiperidin-1-ylmethyl)-2-(tributylstannanyl)thieno[3,2-d]pyrimidine

Product 1

HCID 498331094-(1-((2-(Imidazo[1,2-a]pyridin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)morpholineYield 42.3%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
140 °C

Procedure

A mixture of 4-morpholin-4-yl-6-(4-morpholin-4-ylpiperidin-1-ylmethyl)-2-(tributylstannanyl)thieno[3,2-d]pyrimidine (69 mg, 0.10 mmol), 5-bromoimidazo[1,2-a]pyridine (24 mg, 0.12 mmol), Pd(PPh3)4(11 mg, 0.01 mmol) and copper(I) iodide (23 mg, 0.12 mmol) in THF (1 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 (10 g). The cartridge was washed with MeOH then the product was eluted with 2 M NH3 in MeOH. The appropriate fractions were evaporated and the resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 3:97) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 70:30 to 2:98) to give 687 as a white solid (22 mg, 42%). LCMS (Method F): RT 3.90 min; [M+H]+ 520. 1H NMR (400 MHz, CHCl3-d): δ 9.23 (s, 1 H); 7.95 (dd, J=7.2, 1.2 Hz, 1 H); 7.77 (d, J=8.9 Hz, 1 H); 7.75 (d, J=1.2 Hz, 1 H); 7.35 (s, 1 H); 7.31 (dd, J=8.9, 7.2 Hz, 1 H); 4.07 (t, J=4.7 Hz, 4 H); 3.91 (t, J=4.7 Hz, 4 H); 3.84 (s, 2 H); 3.74 (t, J=4.4 Hz, 4 H); 3.05 (d, J=11.4 Hz, 2 H); 2.57 (t, J=4.4 Hz, 4 H); 2.29-2.19 (m,1 H); 2.15 (t, J=11.4 Hz, 2 H); 1.87 (d, J=12.5 Hz, 2 H); 1.65-1.59 (m, 2 H)

Workup

  1. customwas purged with argon gas
  2. washThe cartridge was washed with MeOH
  3. washthe product was eluted with 2 M NH3 in MeOH
  4. customThe appropriate fractions were evaporated
  5. customthe resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 3:97)

Sources & evidence

ORD record
ord-338c006d049f46e3a291a79879e60142
Source dataset
uspto-grants-2012_05
Patent number
US08173650B2

Reaction notes

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