Diethyl Ether → (1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperidin-4-yl)methyl 6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate

HRID 913937Notes

Reaction equation

HRID 913937 reaction equation
[NH2:1][C:2]1[C:31]([NH2:32])=[CH:30][C:29]([Cl:33])=[CH:28][C:3]=1[C:4]([O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:5].[C:34](N1C=CN=C1)(N1C=CN=C1)=[O:35].C(OCC)C>O1CCCC1>[Cl:33][C:29]1[CH:28]=[C:3]([C:4]([O:6][CH2:7][C:8]2([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)=[O:5])[C:2]2[NH:1][C:34](=[O:35])[NH:32][C:31]=2[CH:30]=1

Participants

5

Reactant 3

HCID 3283Diethyl EtherHCID 682631,1'-Carbonyldiimidazole2×HCID 57545959tert-Butyl 4-((2,3-diamino-5-chlorobenzoyloxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate

Product 1

HCID 57546031(1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperidin-4-yl)methyl 6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
70 °C

Procedure

To a solution of tert-butyl 4-((2,3-diamino-5-chlorobenzoyloxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (714 mg, 1.5 mmol) in tetrahydrofuran (10 mL) at 0° C. was added carbonyldiimidazole (242 mg, 1.5 mmol). The ice bath was removed and stirring continued for 1 h. The reaction was treated with a second portion of carbonyldiimidazole (242 mg, 1.5 mmol) and stirred for 1 h at room temperature. The solution was transferred to a microwave vial and heated at 70° C. for 1 h via microwave. The reaction was poured into diethyl ether, washed with water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25%→100 ethyl acetate/n-hexane) gave 0.52 g (69%) as a brown solid. 1H-NMR (CDCl3, 500 MHz) δ 9.69 (bs, 1H), 9.05 (bs, 1H), 7.42 (d, J=1.8 Hz, 1H), 7.38 (dd, J=8.6, 5.2 Hz, 2H), 7.19 (d, J=1.5 Hz, 1H), 7.11 (dd, J=8.6, 8.5 Hz, 2H), 4.32 (s, 2H), 3.81 (m, 2H), 3.09 (m, 2H), 2.24 (m, 2H), 1.89 (m, 2H), 1.44 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 164.6, 162.6, 160.6, 157.4, 155.1, 136.5, 131.1, 128.8 (d, J=7.7 Hz), 126.0, 121.1, 115.7 (d, J=21 Hz), 114.7, 111.8, 79.8, 73.1, 40.6, 39.9, 31.8, 28.6. Mass spec.: 525.87 (MNa)+.

Workup

  1. customThe ice bath was removed
  2. stirringstirred for 1 h at room temperature
  3. washwashed with water
  4. dry with materialbrine, dried over magnesium sulfate
  5. concentrationconcentrated
  6. customColumn chromatography (25%→100 ethyl acetate/n-hexane) gave 0.52 g (69%) as a brown solid

Sources & evidence

ORD record
ord-528ca156193b42c080c0a5dcd746601b
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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