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 571288Notes

Reaction equation

HRID 571288 reaction equation
[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]

Participants

5

Reactant 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

Product 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-oxideYield 67.5%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

(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.

Workup

  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

Sources & evidence

ORD record
ord-4fc78df08d4e4982b323c9c206f72d67
Source dataset
uspto-grants-2015_05
Patent number
US09024027B2

Reaction notes

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