Diisopropylethylamine → 4-(6-Iodo-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide

HRID 657201Notes

Reaction equation

HRID 657201 reaction equation
[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[N+](C1C=CC([O:27][C:28](=O)[NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH:37]([CH3:39])[CH3:38])=[CH:32][CH:31]=2)=CC=1)([O-])=O.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH:37]([O:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:28]([N:15]2[CH2:16][CH2:17][CH:12]([C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=4)[N:8]=[CH:7][N:6]=3)[CH2:13][CH2:14]2)=[O:27])=[CH:31][CH:32]=1)([CH3:39])[CH3:38]

Participants

5

Reactant 3

HCID 81531Diisopropylethylamine2×HCID 58769998(4-Isopropoxy-phenyl)-carbamic acid 4-nitrophenyl esterHCID 587708326-Iodo-4-piperidin-4-yl-quinazoline

Product 1

HCID 587706604-(6-Iodo-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amideYield 42.3%

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent2×

Procedure

A solution of impure 6-iodo-4-piperidin-4-yl-quinazoline (4.00 g, “11.8 mmol”), as prepared in the preceding step, in CHCl3 (20 mL) was treated with (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (4.10 g, 13.0 mmol), prepared as described in Example 1a, in one portion at rt under air. DIEA (2.15 mL, 13.0 mmol) was then added in one portion, and residual nitrophenyl ester and DIEA was transferred to the reaction with additional CHCl3 (20 mL). After 8 h rt stirring, the reaction was washed in succession with 1 M NaH2PO4 (50 mL) and 2 M K2CO3 (1×50 mL). The organic phase was filtered, the filter cake was washed with DCM (2×10 mL), and the combined filtrates were dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue (1:2 hex/EtOAc) afforded the title compound as a beige foam (2.58 g, 42%). 1H-NMR (300 MHz, CDCl3) δ 9.26 (s, 1H), 8.52 (d, 1H), 8.13 (dd, 1H), 7.80 (d, 1H), 7.25 (m, 2H), 6.83 (m, 2H), 6.33 (br s, 1H), 4.48 (heptet, 1H), 4.32-4.22 (m, 2H), 3.68 (tt, 1H), 3.17 (td, 2H), 2.21-1.92 (m, 4H), 1.32 (d, 6H). LC/MS (ESI): calcd mass 516.1, found 517.2 (MH)+.

Workup

  1. customprepared
  2. customas described in Example 1a, in one portion at rt under air
  3. washthe reaction was washed in succession with 1 M NaH2PO4 (50 mL) and 2 M K2CO3 (1×50 mL)
  4. filtrationThe organic phase was filtered
  5. washthe filter cake was washed with DCM (2×10 mL)
  6. dry with materialthe combined filtrates were dried (Na2SO4)
  7. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-336927d7e6134f6fb60cdb94074790a6
Source dataset
uspto-grants-2011_12
Patent number
US08071768B2

Reaction notes

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