1,2-Dichloroethane → HCID 86681718, compound

HRID 571309Notes

Reaction equation

HRID 571309 reaction equation
FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[C:27](=[O:31])[N:26]([CH2:32][C:33]([OH:35])=[O:34])[C:25]3=[O:36])[S:18]([CH3:21])(=[O:20])=[O:19])[CH2:11][CH2:10]1.[Cl:37][C:38]1[CH:39]=[N+:40]([O-:63])[CH:41]=[C:42]([Cl:62])[C:43]=1[CH2:44][C@@H:45]([C:47]1[CH:52]=[CH:51][C:50]([O:53][CH:54]([F:56])[F:55])=[C:49]([O:57][CH2:58][CH:59]2[CH2:61][CH2:60]2)[CH:48]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:37][C:38]1[CH:39]=[N+:40]([O-:63])[CH:41]=[C:42]([Cl:62])[C:43]=1[CH2:44][C@@H:45]([C:47]1[CH:52]=[CH:51][C:50]([O:53][CH:54]([F:56])[F:55])=[C:49]([O:57][CH2:58][CH:59]2[CH2:61][CH2:60]2)[CH:48]=1)[O:34][C:33](=[O:35])[CH2:32][N:26]1[C:25](=[O:36])[C:24]2[C:28](=[CH:29][CH:30]=[C:22]([N:17]([CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][N:9]([CH3:8])[CH2:14][CH2:13]3)[S:18]([CH3:21])(=[O:20])=[O:19])[CH:23]=2)[C:27]1=[O:31]

Participants

6

Reactant 3

HCID 111,2-Dichloroethane2×HCID 71092687HCID 71092687, compoundHCID 86681716HCID 86681716, compound

Product 1

HCID 86681718HCID 86681718, compoundYield 17.76%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent2×

Procedure

A mixture of 2-(5-(N-(2-(4-methylpiperazin-1-yl)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetic acid 2,2,2-trifluoroacetic acid salt (128 mg, 0.237 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (83 mg, 0.198 mmol), EDC (53.0 mg, 0.277 mmol) and DMAP (48.3 mg, 0.395 mmol) in DCM (4 ml) was stirred at room temperature overnight. Additional EDC (18.93 mg, 0.099 mmol) was added, and the reaction was stirred at the same temperature for further 4 hours. The mixture was diluted with DCM and washed with 1N HCl and brine. The organic phase was dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH 96/4, then DCM/MeOH 92/8) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(N-(2-(4-methylpiperazin-1-yl)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetoxy)-ethyl)pyridine 1-oxide as a white solid (29 mg, 0.035 mmol, 17.76% yield, MS/ESI+ 826.03 [MH]+, [αD]=−23.91, c=0.466, MeOH). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.44 (s, 2H), 7.92-7.99 (m, 2H), 7.88 (dd, 1H), 7.19 (d, 1H), 7.09 (d, 1H), 6.97 (dd, 1H), 7.08 (t, 1H), 6.02 (dd, 1H), 4.43 (s, 2H), 3.95 (dd, 2H), 3.80-3.92 (m, 2H), 3.32-3.45 (m, 1H), 3.17-3.24 (m, 1H), 3.15 (s, 3H), 2.39 (t, 2H), 2.25-2.34 (m, 4H), 2.12-2.22 (m, 4H), 2.07 (s, 3H), 1.15-1.32 (m, 1H), 0.53-0.67 (m, 2H), 0.31-0.45 (m, 2H).

Workup

  1. stirringthe reaction was stirred at the same temperature for further 4 hours
  2. washwashed with 1N HCl and brine
  3. dry with materialThe organic phase was dried over Na2SO4
  4. filtrationfiltered
  5. customevaporated
  6. customThe crude was purified by flash chromatography on silica gel (DCM/MeOH 96/4

Sources & evidence

ORD record
ord-c5c777ee10cf4bb89e8d7a7582a28b48
Source dataset
uspto-grants-2015_05
Patent number
US09024027B2

Reaction notes

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