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

HRID 923269

Reaktionsgleichung

Reaktionsgleichung von HRID 923269
[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

Komponenten

6

Edukt 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

Produkt 1

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

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6344DichloromethaneLösungsmittel2×

Reaktionsbedingungen

Temperatur
0 °C

Versuchsvorschrift

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).

Aufarbeitung

  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)

Quellen und Nachweise

ORD-Eintrag
ord-a049cafdce6145559a66267efb049f2c
Quelldatensatz
uspto-grants-2016_03
Patentnummer
US09278969B2

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