Water → 4-(6,7-Difluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester

HRID 657283Notes

Reaction equation

COC([C:5]1([C:18]2[C:27]3[C:22](=[CH:23][C:24]([F:29])=[C:25]([F:28])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=O.[Li+].[Cl-].O.[Na+].[Cl-]>CS(C)=O>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][CH:5]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([F:29])=[C:25]([F:28])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]

Participants

Conditions

Temperature: 150 °C

Procedure

A mixture of 4-(6,7-Difluoro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (451 mg, 1.11 mmol), as prepared in the previous step, LiCl (89 mg, 2.12 mmol), water (60 μL, 3.3 mmol), and DMSO (430 μL) was stirred at 150° C. for 7.5 hrs with a reflux condenser. The reaction was then allowed to cool to rt, shaken with 1M NaCl (5 mL), and extracted with DCM (1×3 mL) and 9:1 DCM/MeOH (1×3 mL). The organic layers were combined, dried (Na2SO4), and concentrated. The residue was purified by silica flash chromatography (3:1 hex/EtOAc→2:1 eluent) to provide the title compound (151.8 mg, 39%). 1H-NMR (300 MHz, CDCl3) δ 9.22 (s, 1H), 7.90 (dd, 1H), 7.81 (dd, 1H), 4.33 (br m, 2H), 3.50 (tt, 1H), 2.96 (br t, 2H), 2.11-1.82 (m, 4H), 1.49 (s, 9H). LC/MS (ESI): calcd mass 349.2, found 368.3 (MH.H2O)+.

Workup

temperatureto cool to rt
extractionextracted with DCM (1×3 mL) and 9:1 DCM/MeOH (1×3 mL)
dry with materialdried (Na2SO4)
concentrationconcentrated
customThe residue was purified by silica flash chromatography (3:1 hex/EtOAc→2:1 eluent)

Sources & evidence

ORD record: ord-8c8db44afe3f46b68c128141e721062d
Source dataset: uspto-grants-2011_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08071768B2

Reaction notes

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