Carbamate → 2-Nitrophenol

HRID 657251Notes

Reaction equation

HRID 657251 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[N:17][CH:18]=[N:19]3)=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.Cl.[N+:29]([C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39](=O)[NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[CH:43][CH:42]=2)=[CH:34][CH:33]=1)([O-:31])=[O:30].[CH3:54][N:55]([CH3:58])[CH2:56][CH3:57].N1C2C(=CC=CC=2)C=NC=1.C(=O)([O-:71])N>C(Cl)Cl.CO>[N:47]1([C:44]2[CH:43]=[CH:42][C:41]([NH:40][C:39]([N:25]3[CH2:24][CH2:23][CH:22]([C:16]4[C:15]5[C:20](=[CH:21][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:5]6[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]6)=[CH:13][CH:14]=5)[N:19]=[CH:18][N:17]=4)[CH2:27][CH2:26]3)=[O:38])=[CH:46][CH:45]=2)[CH2:48][CH2:49][O:50][CH2:51][CH2:52]1.[N+:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[OH:71])([O-:31])=[O:30].[CH3:54][N:55]([CH3:58])[CH2:56][CH3:57]

Participants

9

Reactant 5

HCID 276CarbamateHCID 9210QuinazolineHCID 11723DimethylethylamineHCID 120037067-[3-(4-Methyl-piperazin-1-yl)-propoxy]-4-piperidin-4-yl-quinazolineHCID 68947764(4-Morpholin-4-yl-phenyl)-carbamic acid 4-nitrophenyl ester hydrochloride

Product 3

HCID 69472-NitrophenolHCID 11723DimethylethylamineHCID 119755244-{7-[3-(4-Methyl-piperazin-1-yl)-propoxy]-quinazolin-4-yl}-piperidine-1-carboxylic acid (4-morpholin-4-yl-phenyl)-amide

Reagents, catalysts & solvents 1

HCID 21226129Dichloromethane methanolSolvent3×

Procedure

A solution of 7-[3-(4-Methyl-piperazin-1-yl)-propoxy]-4-piperidin-4-yl-quinazoline (3.654 g, 9.9 mmol), as prepared in the previous step, in 98:2 DCM/MeOH (15 mL) was added rapidly dropwise under air in 2 mL portions to an ice bath-chilled stirred mixture of (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride (4.13 g, 10.9 mmol), as prepared in Example 66a, and dimethylethylamine (DMEA) (1.4 mL, 13 mmol) in 98:2 DCM/MeOH (20 mL). Residual quinazoline derivative was then transferred to the carbamate reaction mixture with 2×7 mL additional 98:2 DCM/MeOH. The resulting homogeneous dark amber solution was stirred for another 5 min, and the ice bath was then removed and the reaction stirred at “rt” for 1.5 hr. The homogeneous reaction solution was then directly applied to a silica flash column (79 mm diameter×6″ length) pre-equilibrated with acetone. The title compound was eluted with 1.5 L acetone→2 L 9:1 acetone/MeOH→2 L 9:1 acetone/MeOH/3% DMEA. The combined fractions were concentrated to afford the title compound contaminated with nitrophenol and DMEA, and this material was partitioned with DCM (100 mL) and 2 M aqueous K2CO3 (2×20 mL). The organic layer was dried (Na2SO4) and concentrated under high vacuum at 90° C. to afford the title compound as a lavender foam that was crushed to a powder [3.89 g, 70% over three steps from 4-(7-Fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester].

Workup

  1. temperaturebath-chilled
  2. stirringThe resulting homogeneous dark amber solution was stirred for another 5 min
  3. customthe ice bath was then removed
  4. stirringthe reaction stirred at “rt” for 1.5 hr
  5. washThe title compound was eluted with 1.5 L acetone→2 L 9:1 acetone/MeOH→2 L 9:1 acetone/MeOH/3% DMEA
  6. concentrationThe combined fractions were concentrated

Sources & evidence

ORD record
ord-05d2a809decf4363ae8f0ef26f33b174
Source dataset
uspto-grants-2011_12
Patent number
US08071768B2

Reaction notes

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