Propargyl alcohol → 4-[6-(3-Hydroxy-prop-1-ynyl)-quinazolin-4-yl]-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide

HRID 657202Notes

Reaction equation

HRID 657202 reaction equation
[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27](I)[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH2:31]([OH:34])[C:32]#[CH:33].C(NCC)C>[Cu]I.CCOC(C)=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:33]#[C:32][CH2:31][OH:34])[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]

Participants

6

Reactant 3

HCID 7859Propargyl alcoholHCID 8021DiethylamineHCID 587706604-(6-Iodo-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide

Product 1

HCID 587706514-[6-(3-Hydroxy-prop-1-ynyl)-quinazolin-4-yl]-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amideYield 91%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of 4-(6-iodo-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide (1.056 g, 2.05 mmol), as prepared in Example 11d, CuI (3.9 mg, 20.5 μmol), trans-PdCl2[P(C6H5)3]2 (26.8 mg, 38.2 μmol), propargyl alcohol (139 μL, 2.36 mmol), and diethylamine (3.4 mL) was flushed with a stream of argon for 30 s, and then quickly sealed and vigorously stirred at rt under argon for 5 h. The resulting dark brown bilayer was concentrated under reduced pressure at rt, dissolved in DCM (10 mL), and vigorously shaken with 0.75 M EDTA (tetrasodium salt) (1×2 mL). The light green aqueous layer was extracted with DCM (1×10 mL), the organic layers were combined, dried (Na2SO4), and concentrated to give a beige foam soluble in 9:1 EtOAc/DCM (˜5 mL). Flash chromatography (1:9 hex/EtOAc→EtOAc) provided the title compound as a yellow foam (825 mg, 91%). 1H-NMR (300 MHz, CDCl3) δ 9.24 (s, 1H), 8.26 (d, 1H), 8.01 (d, 1H), 7.87 (dd, 1H), 7.25 (m, 2H), 6.85 (m, 2H), 6.33 (br s, 1H), 4.59 (d, 2H), 4.48 (heptet, 1H), 4.32-4.23 (m, 2H), 3.71 (m, 1H), 3.22-3.10 (m, 2H), 2.21-1.94 (m, 5H), 1.32 (d, 6H). LC/MS (ESI): calcd mass 444.2, found 445.2 (MH)+.

Workup

  1. customwas flushed with a stream of argon for 30 s
  2. customquickly sealed
  3. concentrationThe resulting dark brown bilayer was concentrated under reduced pressure at rt
  4. dissolutiondissolved in DCM (10 mL)
  5. stirringvigorously shaken with 0.75 M EDTA (tetrasodium salt) (1×2 mL)
  6. extractionThe light green aqueous layer was extracted with DCM (1×10 mL)
  7. dry with materialdried (Na2SO4)
  8. concentrationconcentrated
  9. customto give a beige foam soluble in 9:1 EtOAc/DCM (˜5 mL)

Sources & evidence

ORD record
ord-a93c8649207c43319a28817956147cf2
Source dataset
uspto-grants-2011_12
Patent number
US08071768B2

Reaction notes

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