Methanesulfonyl chloride → Methanesulfonic acid 3-{4-[1-(4-isopropoxy-phenylcarbamoyl)-piperidin-4-yl]-quinazolin-6-yl}-prop-2-ynyl ester

HRID 657203Notes

Reaction equation

HRID 657203 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]([C:30]#[C:31][CH2:32][OH:33])[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].CCN(C(C)C)C(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]#[C:31][CH2:32][O:33][S:44]([CH3:43])(=[O:46])=[O:45])[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:18][CH2:19]2)=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]

Participants

5

Reactant 3

HCID 31297Methanesulfonyl chlorideHCID 81531DiisopropylethylamineHCID 587706514-[6-(3-Hydroxy-prop-1-ynyl)-quinazolin-4-yl]-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide

Product 1

HCID 58770853Methanesulfonic acid 3-{4-[1-(4-isopropoxy-phenylcarbamoyl)-piperidin-4-yl]-quinazolin-6-yl}-prop-2-ynyl esterYield 93.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 4-[6-(3-hydroxy-prop-1-ynyl)-quinazolin-4-yl]-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide (816 mg, 1.84 mmol), as prepared in Example 12, and DIEA (350 μL, 2.12 mmol) in DCM (13 mL) was treated with methanesulfonyl chloride (157 μL, 2.02 mmol) dropwise over 1 min with stirring at 0° C. under positive argon pressure. The ice bath was immediately removed, and the reaction was stirred at rt for 1 h 15 min. Flash chromatographic purification of the crude reaction mixture (1:9 hex/EtOAc→EtOAc) afforded the title compound (896 mg, 93%). 1H-NMR (300 MHz, CDCl3) δ 9.27 (s, 1H), 8.31 (d, 1H), 8.04 (d, 1H), 7.89 (dd, 1H), 7.26 (m, 2H), 6.85 (m, 2H), 6.34 (br s, 1H), 5.15 (s, 2H), 4.49 (heptet, 1H), 4.33-4.23 (m, 2H), 3.73 (m, 1H), 3.25-3.11 (m, 2H), 3.18 (s, 3H), 2.22-1.94 (m, 4H), 1.32 (d, 6H). LC/MS (ESI): calcd mass 522.2, found 523.3 (MH)+.

Workup

  1. customThe ice bath was immediately removed
  2. stirringthe reaction was stirred at rt for 1 h 15 min
  3. customFlash chromatographic purification of the crude
  4. customreaction mixture (1:9 hex/EtOAc→EtOAc)

Sources & evidence

ORD record
ord-331ab806557b4db882d9541fff190a2f
Source dataset
uspto-grants-2011_12
Patent number
US08071768B2

Reaction notes

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