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

HRID 657215Notes

Reaction equation

HRID 657215 reaction equation
[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N+](C1C=CC([O:36][C:37](=O)[NH:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH:46]([CH3:48])[CH3:47])=[CH:41][CH:40]=2)=CC=1)([O-])=O>CO>[CH:46]([O:45][C:42]1[CH:43]=[CH:44][C:39]([NH:38][C:37]([N:15]2[CH2:16][CH2:17][CH:12]([C:6]3[C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:13][CH2:14]2)=[O:36])=[CH:40][CH:41]=1)([CH3:48])[CH3:47]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 58769998(4-Isopropoxy-phenyl)-carbamic acid 4-nitrophenyl esterHCID 595516814-(7-Chloro-quinazolin-4-yl)-piperidine

Product 1

HCID 587707964-(7-Chloro-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amideYield 12%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

Solid KOH (224 mg, 4 mmol) was added to a suspension 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) in a 1:1 mixture of dioxane and water (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-chloro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (29b). 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-chloro-quinazolin-4-yl)-piperidine (29c) as a di-HCl salt. To a suspension of (29c) in anhydrous MeOH, was added DIEA (45 μL, 0.25 mmol) followed by (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (48 mg, 0.15 mmol) 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 mg (12% overall yield from 29a) of pure 4-(7-chloro-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide. 1H-NMR (300 MHz, CDCl3): δ 9.25 (s, 1H), 8.15-8.06 (m, 2H), 7.62 (d, 1H), 7.23 (d, 2H), 6.85 (d, 2H), 6.30 (s, 1H), 4.49 (m, 1H), 4.26 (m, 2H), 3.70 (m, 1H), 3.15 (m, 2H), 2.23-2.05 (m, 2H), 2.05-1.92 (m, 2H), 1.32 (d, 6H). LC/MS (ESI): calcd mass 424.2, found 425.4 (MH)+.

Workup

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

Sources & evidence

ORD record
ord-5e70fe88617f42cfb251a34bce1f8c46
Source dataset
uspto-grants-2011_12
Patent number
US08071768B2

Reaction notes

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