Piperazine → 4-(7-Piperazin-1-yl-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester

HRID 657265Notes

Reaction equation

HRID 657265 reaction equation
[NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26](F)=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>CS(C)=O.O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([N:1]4[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]4)=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]

Participants

5

Reactant 2

HCID 4837PiperazineHCID 595517364-(7-Fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 595516924-(7-Piperazin-1-yl-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of piperazine (5 mmol) and 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (1 mmol) in DMSO (1 mL) was stirred at 120° C. for 1 h. It was then diluted with water and extracted with DCM. The combined extracts were washed with water, brine, dried (anhydrous MgSO4), filtered and concentrated in vacuo to obtain 4-(7-piperazin-1-yl-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester. This (0.1 mmol) was dissolved in anhydrous DCM (1 mL) and treated with Et3N (0.2 mmol) followed by 9-fluorenylmethyl chloroformate (FMOC-Cl, 0.2 mmol) and the mixture was stirred at rt overnight and then washed with water thrice, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. To this was then added 3M HCl/MeOH (2 mL) and stirred at rt for 2 h and then concentrated in vacuo. The crude residue was dissolved in a mixture of DCM:MeOH (1:1; 2 mL) and neutralized with excess Et3N and treated with (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitrophenyl ester hydrochloride (0.11 mmol), as prepared by the method outlined in Example 66a, at rt overnight. It was then concentrated in vacuo and the crude product was dissolved in DCM and washed with water thrice, then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was then purified by Preparative TLC (silica gel; DCM:MeOH:NH4OH, 90:9:1) to obtain 5.6 mg (11%) of the title compound. 1H-NMR (300 MHz, CDCl3): 9.04 (s, 1H), 7.97 (d, 1H), 7.36-7.18 (m, 4H), 6.88 (d, 2H), 6.31 (s, 1H), 4.25 (m, 2H), 3.89-3.82 (m, 4H), 3.70-3.56 (m, 1H), 3.46-3.38 (m, 4H), 3.19-3.04 (m, 10H), 2.21-1.90 (m, 5H). LC/MS (ESI): 502.1 (MH)+.

Workup

  1. extractionextracted with DCM
  2. washThe combined extracts were washed with water, brine
  3. dry with materialdried (anhydrous MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-db62b342e4c4479b86e8acade0b6f223
Source dataset
uspto-grants-2011_12
Patent number
US08071768B2

Reaction notes

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