Lithium Chloride → 4-(7-Fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester

HRID 657239Notes

Reaction equation

HRID 657239 reaction equation
COC([C:5]1([C:18]2[C:27]3[C:22](=[CH:23][C:24]([F:28])=[CH:25][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-].C([O-])(O)=O.[Na+]>O.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:28])=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]

Participants

6

Reactant 3

HCID 433294Lithium ChlorideHCID 516892Sodium BicarbonateHCID 595517614-(7-Fluoro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester

Product 1

HCID 595517364-(7-Fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent2×

Procedure

A mixture of 4-(7-fluoro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (“6.83 g”), as prepared without further purification in the previous step, LiCl (1.32 g, 31.1 mmol), water (832 μL, 46.2 mmol), and DMSO (6.0 mL) was stirred under air at 150° C. (oil bath) with an efficient condenser (to retain reagent water) for 9.5 h. The dark solution was then allowed to cool to rt, shaken with 1.0 M NaHCO3, and extracted with EtOAc (1×60 mL) and 9:1 DCM/MeOH (2×30 mL). The organic layers were combined, dried (Na2SO4), and concentrated to afford a thick clear amber oil. Flash chromatography of this residue (3:2 hexanes/EtOAc) afforded the title compound as a thick clear yellow syrup that was rubbed to a beige solid (2.37 g, 46% from 4-chloro-7-fluoroquinazoline). 1H-NMR (300 MHz, CDCl3) δ 9.23 (s, 1H), 8.20 (dd, 1H), 7.67 (dd, 1H), 7.42 (ddd, 1H), 4.42-4.25 (br m, 2H), 3.65 (m, 1H), 2.96 (m, 2H), 2.14-1.83 (m, 4H), 1.49 (s, 1H). LC/MS (ESI): calcd mass 331.2, found 332.1 (MH)+ (weak).

Workup

  1. extractionextracted with EtOAc (1×60 mL) and 9:1 DCM/MeOH (2×30 mL)
  2. dry with materialdried (Na2SO4)
  3. concentrationconcentrated
  4. customto afford a thick clear amber oil

Sources & evidence

ORD record
ord-99767985acce49979442ebb198042d5b
Source dataset
uspto-grants-2011_12
Patent number
US08071768B2

Reaction notes

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