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

HRID 1877950

反応式

HRID 1877950 の反応式
[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

参加物

6

反応物 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

生成物 1

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

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒2 回

反応条件

温度
0 °C

実験手順

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, 3 H), 2.76-2.88 (m, 2 H), 2.95-3.04 (m, 1 H), 3.57-3.69 (m, 1 H), 3.74 (s, 3 H), 4.43 (d, J=14.4 Hz, 1 H), 4.58-4.70 (m, 1 H), 6.79 (s, 1 H), 6.86-6.94 (m, 1 H), 6.96-7.05 (m, 2 H), 7.10 (s, 1 H), 7.19-7.25 (m, 3 H), 7.55 (s, 1 H). 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).

後処理

  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)

出典と根拠

ORDレコード
ord-fa0a6c9052d24b26aee9dc67d3c0d495
出典データセット
uspto-grants-2012_11
特許番号
US08314097B2

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