tert-Butyl 4-bromo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate → 2-methyl-2-(4-((7-methyl-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propanamide

HRID 1923306Notes

Reaction equation

HRID 1923306 reaction equation
[CH3:1][C:2]1[C:6]2[N:7]=[C:8]([Sn](CCCC)(CCCC)CCCC)[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]=2[S:4][C:3]=1[CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]([CH3:42])([CH3:41])[C:38]([NH2:40])=[O:39])[CH2:33][CH2:32]1.C(OC([N:50]1[C:54]2=[N:55][CH:56]=[CH:57][C:58](Br)=[C:53]2[CH:52]=[CH:51]1)=O)(C)(C)C>C1(C)C=CC=CC=1.[Cu]I>[CH3:42][C:37]([N:34]1[CH2:35][CH2:36][N:31]([CH2:30][C:3]2[S:4][C:5]3[C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[N:9][C:8]([C:58]4[CH:57]=[CH:56][N:55]=[C:54]5[NH:50][CH:51]=[CH:52][C:53]=45)=[N:7][C:6]=3[C:2]=2[CH3:1])[CH2:32][CH2:33]1)([CH3:41])[C:38]([NH2:40])=[O:39]

Participants

5

Reactant 2

HCID 58298320tert-Butyl 4-bromo-1H-pyrrolo[2,3-b]pyridine-1-carboxylateHCID 596034662-[4-(7-Methyl-4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide

Product 1

HCID 596054792-methyl-2-(4-((7-methyl-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propanamideYield 24%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 1140TolueneSolvent

Procedure

A mixture of 2-[4-(7-methyl-4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (200 mg, 0.28 mmol), 4-bromo-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butylester (100 mg, 0.34 mmol), Pd(Ph3)4 (33 mg, 0.028 mmol) and CuI (65 mg, 0.34 mmol) in toluene (5 mL) was purged with argon, then subjected to microwave irradiation at 140° C. for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The residue was then dissolved in DCM/TFA (8 mL/8 mL) and stirred for 2 h at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 05:95) to give 696 as a white powder (0.036 g, 24%). LCMS (Method F): RT 5.68 min, [M+H]+ 535.2. 1H NMR (CDCl3, 400 MHz) δ 9.42-8.74 (m, 1 H); 8.59-7.95 (m, 1 H); 7.92-7.49 (m, 1 H); 7.46-7.35 (m, 2 H); 7.14-7.06 (m, 1 H); 5.27 (s, 1 H); 4.09 (t, J=4.2 Hz, 4); 3.92 (t, J=4.2 Hz, 4 H); 3.85 (s, 2 H); 2.66-2.61 (m, 4 H); 2.53 (s, 3 H); 1.63-1.58 (m, 4 H); 1.26 (s, 6 H)

Workup

  1. customwas purged with argon
  2. customirradiation at 140° C. for 30 min
  3. washThe cartridge was washed with MeOH
  4. washthe desired product was eluted
  5. dissolutionThe residue was then dissolved in DCM/TFA (8 mL/8 mL)
  6. washThe cartridge was washed with MeOH
  7. washthe desired product was eluted
  8. customThe residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 05:95)

Sources & evidence

ORD record
ord-39dbe3841447422ba11559b7d4be7d5f
Source dataset
uspto-grants-2012_05
Patent number
US08173650B2

Reaction notes

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