Dimethylformamide → 5-(4-cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid (4-fluorobenzyl)methylamide

HRID 76888

Reaction equation

HRID 76888 reaction equation
[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:17]([OH:19])=O)[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[CH2:11][CH2:10]2)=[C:5]([O:20][CH3:21])[CH:4]=1)#[N:2].C[N:23]([CH:25]=O)C.C(Cl)(=O)C(Cl)=O.[F:33][C:34]1[CH:42]=[CH:41][C:37]([CH2:38]NC)=[CH:36][CH:35]=1>C(Cl)Cl>[F:33][C:34]1[CH:42]=[CH:41][C:37]([CH2:38][CH2:25][NH:23][C:17]([C:9]2([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[O:20][CH3:21])[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[CH2:11][CH2:10]2)=[O:19])=[CH:36][CH:35]=1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 65578Oxalyl chlorideHCID 7368601-(4-fluorophenyl)-N-methylmethanamineHCID 588271205-(4-cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid

Product 1

HCID 668983325-(4-cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid (4-fluorobenzyl)methylamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

Crude 5-(4-cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid (0.168 g, 0.59 mmol) is suspended in CH2Cl2 (3 mL) and cooled to 0° C. To it is added DMF (0.2 mL) followed by the addition of a CH2Cl2 solution of oxalyl chloride (0.6 mL, 2.0 M). After 2 h, 4-fluoro-N-methylbenzylamine (0.23 mL, 1.78 mmol) is added. The reaction is stirred for another 2 h, evaporated to dryness, and partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase is dried (Na2SO4), filtered, and concentrated. The crude residue is purified via flash column chromatography (2-5% MeOH/CH2Cl2) to give 5-(4-cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid (4-fluorobenzyl)methylamide as a yellow solid. MS (ESI) m/z 405.2 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 2.60 (s, 3H), 2.76-2.88 (m, 2H), 2.95-3.04 (m, 1H), 3.57-3.69 (m, 1H), 3.74 (s, 3H), 4.43 (d, J=14.4 Hz, 1H), 4.58-4.70 (m, 1H), 6.79 (s, 1H), 6.86-6.94 (m, 1H), 6.96-7.05 (m, 2H), 7.10 (s, 1H), 7.19-7.25 (m, 3H), 7.55 (s, 1H). Resolution of the (R) and (S) enantiomers of the title compound is achieved by chiral HPLC using ChiralPak AD column with a 6:4 EtOH/hexane mobile phase to give enantiomer A (tr=30.2 min) and enantiomer B (tr=36.0 min).

Workup

  1. customevaporated to dryness
  2. custompartitioned between EtOAc and saturated aqueous NaHCO3
  3. dry with materialThe organic phase is dried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude residue is purified via flash column chromatography (2-5% MeOH/CH2Cl2)

Sources & evidence

ORD record
ord-5814f6d68c2f4f0fb08e277f282036fa
Source dataset
uspto-grants-2014_09
Patent number
US08835646B2

Linked notes

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