Diisopropylethylamine → 4-(7-Methoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide

HRID 657217Notes

Reaction equation

HRID 657217 reaction equation
[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[N+](C1C=CC([O:37][C:38](=O)[NH:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH:47]([CH3:49])[CH3:48])=[CH:42][CH:41]=2)=CC=1)([O-])=O>CO>[CH:47]([O:46][C:43]1[CH:44]=[CH:45][C:40]([NH:39][C:38]([N:16]2[CH2:17][CH2:18][CH:13]([C:7]3[C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:10]=[CH:9][N:8]=3)[CH2:14][CH2:15]2)=[O:37])=[CH:41][CH:42]=1)([CH3:49])[CH3:48]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 58769998(4-Isopropoxy-phenyl)-carbamic acid 4-nitrophenyl esterHCID 595517044-(7-Methoxy-quinazolin-4-yl)-piperidine

Product 1

HCID 587706354-(7-Methoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amideYield 13%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

Solid KOH (224 mg, 4 mmol) was added to a solution of 4-(7-chloro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (29a; 41 mg, 0.1 mmol), prepared as described in Example 29, in anhydrous MeOH (1 mL). The mixture was stirred at 100° C. for 3 h. It was then cooled to rt and concentrated in vacuo. The residue was dissolved in DCM and washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain crude 4-(7-methoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (31a). This was dissolved in 2 mL of 3M HCl/MeOH was stirred at rt for 1 h and then concentrated in vacuo to obtain crude 4-(7-methoxy-quinazolin-4-yl)-piperidine (31b) as a di-HCl salt. To a suspension of (31b) in anhydrous MeOH (2 mL), was added DIEA (45 μL, 0.25 mmol) followed by (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (48 mg, 0.15 mmol), as prepared in Example 1a, and the mixture was stirred at rt for 1 h. It was then concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 1% MeOH/DCM) to obtain 5.4 mg (13% overall yield from 29a) of pure 4-(7-methoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide. 1H-NMR (300 MHz, CDCl3): δ 9.14 (s, 1H), 8.06 (d, 1H), 7.35 (d, 1H), 7.30-7.25 (m, 3H), 6.84 (d, 2H), 6.30 (s, 1H), 4.48 (m, 1H), 4.26 (m, 2H), 3.99 (s, 3H), 3.69 (m, 1H), 3.14 (m, 2H), 2.23-2.05 (m, 2H), 2.03-1.92 (m, 2H), 1.31 (d, 6H). LC/MS (ESI): calcd mass 420.2, found 421.4 (MH)+.

Workup

  1. customas prepared in Example 1a
  2. concentrationIt was then concentrated in vacuo
  3. customthe residue was purified by flash column chromatography (silica gel, 1% MeOH/DCM)

Sources & evidence

ORD record
ord-229a75e8f3da42c886fac1b9da4efec6
Source dataset
uspto-grants-2011_12
Patent number
US08071768B2

Reaction notes

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