Diisopropylethylamine → 4-{7-[3-(2-Oxo-pyrrolidin-1-yl)-propoxy]-quinazolin-4-yl}-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide

HRID 657244Notes

Reaction equation

HRID 657244 reaction equation
C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][C:29]4=[O:33])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.[N+](C1C=CC(OC(=O)[NH:55][C:56]2[CH:61]=[CH:60][C:59]([O:62][CH:63]([CH3:65])[CH3:64])=[CH:58][CH:57]=2)=CC=1)([O-])=O.CCN(C(C)C)C(C)C>CC#N>[CH:63]([O:62][C:59]1[CH:60]=[CH:61][C:56]([NH:55][C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]5[CH2:32][CH2:31][CH2:30][C:29]5=[O:33])=[CH:21][CH:22]=4)[N:17]=[CH:16][N:15]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:57][CH:58]=1)([CH3:65])[CH3:64]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 21863450Trifluoroacetic acid methylene chlorideHCID 58769998(4-Isopropoxy-phenyl)-carbamic acid 4-nitrophenyl esterHCID 595517034-{7-[3-(2-Oxo-pyrrolidin-1-yl)-propoxy]-quinazolin-4-yl}-piperidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 587706714-{7-[3-(2-Oxo-pyrrolidin-1-yl)-propoxy]-quinazolin-4-yl}-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amideYield 89%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
95 °C

Procedure

4-{7-[3-(2-Oxo-pyrrolidin-1-yl)-propoxy]-quinazolin-4-yl}-piperidine-1-carboxylic acid tert-butyl ester (as prepared in the previous step, 0.20 mmol) was treated with 50% TFA/CH2Cl2 (4 mL) for 2 h and the solvents were evaporated. To the residue was added (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (70.2 mg, 0.22 mmol), as prepared in Example 1a, followed by DIEA (130.5 mg, 1.01 mmol) in CH3CN (4 mL). The resulting mixture was heated at 95° C. for 1 h and the solvents were evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (5% MeOH/EtOAc as eluent) to afford the product as a white solid (95.5 mg, 89% yield). 1H NMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 8.06 (d, J=9.33 Hz, 1H), 7.33 (d, J=2.46 Hz, 1H), 7.28 (dd, J=9.30 and 2.65 Hz, 1H), 7.25 (m, 2H), 6.84 (d, J=8.93 Hz, 2H), 6.33 (br, 1H), 4.48 (m, 1H), 4.26 (m, 2H), 4.17 (t, J=6.10 Hz, 2H), 3.69 (m, 1H), 3.53 (t, J=6.99 Hz, 2H), 3.45 (t, J=7.02 Hz, 2H), 3.13 (td, J=12.85 and 2.83 Hz, 2H), 2.40 (t, J=7.78 Hz, 2H), 1.94-2.20 (m, 8H), 1.31 (d, J=6.06 Hz, 6H). LC-MS (ESI) calcd for C30H38N5O4 (MH+) 532.3, found 532.2. Anal. Calcd for C30H37N5O4: C, 67.77; H, 7.01; N, 13.17. Found: C, 67.81; H, 6.96; N, 13.16.

Workup

  1. customthe solvents were evaporated
  2. customas prepared in Example 1a
  3. customthe solvents were evaporated under reduced pressure
  4. customThe residue was purified by flash column chromatography on silica gel (5% MeOH/EtOAc as eluent)

Sources & evidence

ORD record
ord-0bd108dda7c8436d806fe6679c956887
Source dataset
uspto-grants-2011_12
Patent number
US08071768B2

Reaction notes

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