3-(4-Methyl-1-piperazine)propan-1-ol → 4-{6-Fluoro-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinazolin-4-yl}-piperidine-1-carboxylic acid tert-butyl ester

HRID 657284Notes

Reaction equation

HRID 657284 reaction equation
CC([O-])(C)C.[K+].[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)=[C:27]([F:30])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][CH2:41][OH:42])[CH2:35][CH2:34]1>C1COCC1>[C:7]([O:11][C:12]([N:14]1[CH2:15][CH2:16][CH:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:42][CH2:41][CH2:40][CH2:39][N:36]4[CH2:35][CH2:34][N:33]([CH3:32])[CH2:38][CH2:37]4)=[C:27]([F:30])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:18][CH2:19]1)=[O:13])([CH3:9])([CH3:8])[CH3:10]

Participants

5

Reactant 3

HCID 792083-(4-Methyl-1-piperazine)propan-1-olHCID 23665647Potassium tert-butoxideHCID 595516914-(6,7-Difluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 595517194-{6-Fluoro-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinazolin-4-yl}-piperidine-1-carboxylic acid tert-butyl esterYield 61.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

A solution of 1.19M KOtBu in THF (128 μL, 152 μmol) was added dropwise with stirring over 2.5 min to a 0° C. homogeneous solution of 4-(6,7-Difluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (38.1 mg, 109 μmol), as prepared in the previous step, and 3-(4-Methyl-piperazin-1-yl)-propan-1-ol (22.4 mg, 142 μmol) in THF (170 μL). The reaction was stirred at 0° C. for 1.5 hr, and was then partitioned with DCM (2 mL) and 1M NaCl (2 mL). The aq layer was back-extracted with DCM (1×2 mL), and the combined cloudy white organic layers were dried (Na2SO4) and concentrated. The residue was purified by silica flash chromatography (1:2 hex/EtOAc/3% DMEA eluent) to yield the title compound as an off-white foam (32.6 mg, 61%). NOe experiments support the assigned regioisomer. Select 1H-NMR resonances and nOes (300 MHz, CDCl3) δ 7.73 (d, J=11.4 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 3.46 (tt, 1H). Irradiation of the diagnostic methine proton at δ 3.46 generates an nOe to the quinazoline C5 proton at δ 7.73, but not to the quinazoline C8 proton at δ 7.43. The C5 proton has a larger coupling constant than the C8 proton, indicating fluorine substitution at C6 of the quinazoline. LC/MS (ESI): calcd mass 487.3, found 488.3 (MH)+.

Workup

  1. customwas then partitioned with DCM (2 mL) and 1M NaCl (2 mL)
  2. extractionThe aq layer was back-extracted with DCM (1×2 mL)
  3. dry with materialthe combined cloudy white organic layers were dried (Na2SO4)
  4. concentrationconcentrated
  5. customThe residue was purified by silica flash chromatography (1:2 hex/EtOAc/3% DMEA eluent)

Sources & evidence

ORD record
ord-4d3306dfcacf4e26b8f0c72e7d9ede36
Source dataset
uspto-grants-2011_12
Patent number
US08071768B2

Reaction notes

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