1,2-Dichloroethane → (S)-4-(2-(3-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoyloxy)propanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide

HRID 1776522Notes

Reaction equation

HRID 1776522 reaction equation
[Cl:1][C:2]1[CH:3]=[N+:4]([O-:32])[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@@H:9]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH:23]([F:25])[F:24])=[C:18]([O:26][CH2:27][CH:28]2[CH2:30][CH2:29]2)[CH:17]=1)[O:10][C:11](=[O:15])[CH2:12][CH2:13][OH:14].[C:33]([O:37][C:38]([N:40]([C:45]1[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][C:46]=1[O:54][CH2:55][CH:56]1[CH2:58][CH2:57]1)[S:41]([CH3:44])(=[O:43])=[O:42])=[O:39])([CH3:36])([CH3:35])[CH3:34].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:33]([O:37][C:38]([N:40]([C:45]1[CH:53]=[CH:52][C:48]([C:49]([O:14][CH2:13][CH2:12][C:11]([O:10][C@H:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([F:25])[F:24])=[C:18]([O:26][CH2:27][CH:28]3[CH2:30][CH2:29]3)[CH:17]=2)[CH2:8][C:7]2[C:2]([Cl:1])=[CH:3][N+:4]([O-:32])=[CH:5][C:6]=2[Cl:31])=[O:15])=[O:50])=[CH:47][C:46]=1[O:54][CH2:55][CH:56]1[CH2:57][CH2:58]1)[S:41]([CH3:44])(=[O:43])=[O:42])=[O:39])([CH3:36])([CH3:34])[CH3:35]

Participants

6

Reactant 3

HCID 111,2-DichloroethaneHCID 497657284-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoic acidHCID 86679477(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(3-hydroxy propanoyloxy)ethyl)pyridine 1-oxide

Product 1

HCID 89455835(S)-4-(2-(3-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoyloxy)propanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxideYield 83%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent

Procedure

To a solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-hydroxypropanoyloxy)ethyl)pyridine 1-oxide (0.311 g, 0.632 mmol), 4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoic acid (0.243 g, 0.632 mmol), and EDC (0.363 g, 1.895 mmol) in dry DCM (15 ml), DMAP (0.077 g, 0.632 mmol) was added and the resulting mixture was stirred at RT for 3 hours. The solvent was evaporated, and the residue was partitioned between EtOAc and a NaHCO3 sat. sol. The organic layer was washed with brine and dried over Na2SO4. The solvent was removed and the residue was purified by flash chromatography on silica gel column (DCM:MeOH:32% NH4OH=95:5:0.5) affording (S)-4-(2-(3-(4-(N-(tert-butoxycarbonyl)-methylsulfonamido)-3-(cyclopropylmethoxy)benzoyloxy)propanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.450 g, 0.523 mmol, 83% yield, MS/ESI+ 859.0 [MH]+).

Workup

  1. customThe solvent was evaporated
  2. customthe residue was partitioned between EtOAc
  3. washa NaHCO3 sat. sol. The organic layer was washed with brine
  4. dry with materialdried over Na2SO4
  5. customThe solvent was removed
  6. customthe residue was purified by flash chromatography on silica gel column (DCM:MeOH:32% NH4OH=95:5:0.5)

Sources & evidence

ORD record
ord-3ace6cb0a8e74dd182d245ea849348f1
Source dataset
uspto-grants-2016_02
Patent number
US09265768B2

Reaction notes

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