Methanol → 4-(7-Methoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester

HRID 657216Notes

Reaction equation

HRID 657216 reaction equation
[OH-:1].[K+].C(OC1C=CC(N[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[C:31]4[C:26](=[CH:27][C:28](Cl)=[CH:29][CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=CC=1)(C)C.[CH3:33][OH:34]>>[C:19]([O:1][C:14]([N:16]1[CH2:17][CH2:18][CH:19]([C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:33])=[CH:29][CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH2:20][CH2:21]1)=[O:15])([CH3:22])([CH3:20])[CH3:18]

Participants

4

Reactant 3

HCID 887MethanolHCID 14797Potassium HydroxideHCID 587707964-(7-Chloro-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide

Product 1

HCID 686979944-(7-Methoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester

Conditions

Temperature
100 °C

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. customprepared
  2. temperatureIt was then cooled to rt
  3. concentrationconcentrated in vacuo
  4. dissolutionThe residue was dissolved in DCM
  5. washwashed with water, brine
  6. dry with materialdried over anhydrous MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-40a28d0a0f524befaada4e57231c759e
Source dataset
uspto-grants-2011_12
Patent number
US08071768B2

Reaction notes

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