Methoxyacetyl chloride → (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-(2-methoxyacetamido)-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide

HRID 571288Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 571288
[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:42])[N:5]([CH2:12][C:13]([O:15][C@H:16]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH2:38][CH:39]3[CH2:41][CH2:40]3)[CH:28]=1)[CH2:17][C:18]1[C:23]([Cl:24])=[CH:22][N+:21]([O-:25])=[CH:20][C:19]=1[Cl:26])=[O:14])[C:6]2=[O:11].[CH3:43][O:44][CH2:45][C:46](Cl)=[O:47]>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:24][C:23]1[CH:22]=[N+:21]([O-:25])[CH:20]=[C:19]([Cl:26])[C:18]=1[CH2:17][C@@H:16]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:35])[F:36])=[C:29]([O:37][CH2:38][CH:39]2[CH2:40][CH2:41]2)[CH:28]=1)[O:15][C:13](=[O:14])[CH2:12][N:5]1[C:4](=[O:42])[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[NH:1][C:46](=[O:47])[CH2:45][O:44][CH3:43])[C:6]1=[O:11]

Komponenten

5

Edukt 2

HCID 96623Methoxyacetyl chlorideHCID 86681605(S)-4-(2-(2-(4-amino-1,3-dioxoisoindolin-2-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4 (difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide

Produkt 1

HCID 71553991(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-(2-methoxyacetamido)-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxideAusbeute 67,5 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 142844-(Dimethylamino)pyridineKatalysatorHCID 6228DimethylformamideLösungsmittel

Reaktionsbedingungen

Temperatur
0 °C

Versuchsvorschrift

(S)-4-(2-(2-(4-amino-1,3-dioxoisoindolin-2-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4 (difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (20.0 mg; 0.032 mmol) was dissolved in DMF (2 ml) and cooled down to 0° C. in a ice bath. 2-methoxyacetyl chloride (20.0 mg; 0.184 mmol) and DMAP (0.048 mmol; 5.89 mg) were added to the reaction solution that was stirred a 0° C. for 2 hours. After that time, the reaction was quenched with aqueous HCl (1M) (20 ml) and extracted with EtOAc (20 ml). The organic phase was further washed with HCl (1M) (3×20 ml), dried over Na2SO4 and the solvent removed under reduced pressure to afford the titled compound (15.0 mg; 67% yield). 1H NMR (400 MHz, acetone) δ ppm 10.33-10.47 (m, 1H), 8.80-8.93 (m, 1H), 8.22 (s, 2H), 7.83-7.95 (m, 1H), 7.57-7.67 (m, 1H), 7.16-7.24 (m, 2H), 7.04-7.11 (m, 1H), 6.94 (t, J=75.00 Hz, 1H), 6.13-6.22 (m, 1H), 4.46 (s, 2H), 4.14 (d, J=3.09 Hz, 2H), 3.91-4.06 (m, 2H), 3.65 (s, 3H), 3.49-3.58 (m, 1H), 3.26-3.38 (m, 1H), 1.17-1.39 (m, 1H), 0.54-0.69 (m, 2H), 0.36-0.48 (m, 2H). MS/ESI+ [MH]+=694.1.

Aufarbeitung

  1. customAfter that time, the reaction was quenched with aqueous HCl (1M) (20 ml)
  2. extractionextracted with EtOAc (20 ml)
  3. washThe organic phase was further washed with HCl (1M) (3×20 ml)
  4. dry with materialdried over Na2SO4
  5. customthe solvent removed under reduced pressure

Quellen und Nachweise

ORD-Eintrag
ord-4fc78df08d4e4982b323c9c206f72d67
Quelldatensatz
uspto-grants-2015_05
Patentnummer
US09024027B2

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