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

HRID 1776516Notes

Reaction equation

HRID 1776516 reaction equation
[C:1]([O:5][C:6]([N:8]([C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])=[CH:15][C:14]=1[O:26][CH2:27][CH:28]1[CH2:30][CH2:29]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:33]=[N+:34]([O-:57])[CH:35]=[C:36]([Cl:56])[C:37]=1[CH2:38][C@@H:39]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH:48]([F:50])[F:49])=[C:43]([O:51][CH2:52][CH:53]2[CH2:55][CH2:54]2)[CH:42]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][CH2:20][C:21]([O:23][C@H:39]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH:48]([F:49])[F:50])=[C:43]([O:51][CH2:52][CH:53]3[CH2:54][CH2:55]3)[CH:42]=2)[CH2:38][C:37]2[C:36]([Cl:56])=[CH:35][N+:34]([O-:57])=[CH:33][C:32]=2[Cl:31])=[O:22])=[O:18])=[CH:15][C:14]=1[O:26][CH2:27][CH:28]1[CH2:29][CH2:30]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 3

HCID 111,2-DichloroethaneHCID 71092687(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxideHCID 894599232-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)-benzoyloxy)acetic acid

Product 1

HCID 89459927(S)-4-(2-(2-(4-(N-(tert-butoxycarbonyl)methyl-sulfonamido)-3-(cyclopropylmethoxy)benzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxideYield 78%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent

Procedure

2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)-benzoyloxy)acetic acid (1.7 g, 3.83 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (1.611 g, 3.83 mmol), EDC (2.205 g, 11.50 mmol), and DMAP (0.702 g, 5.75 mmol) were dissolved in DCM (60 ml); the mixture was stirred at RT for 2 days. Then it was concentrated to about half volume, diluted with EtOAc (about 200 ml) and washed with HCl 1N and NaHCO3 sat. sol. The organic layer was dried over Na2SO4, and the solvent was evaporated to dryness. The crude (3.35 g) was purified by flash chromatography on silica gel (eluent: Et20/EtOAc 2/1); (S)-4-(2-(2-(4-(N-(tert-butoxycarbonyl)methyl-sulfonamido)-3-(cyclopropylmethoxy)benzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide was obtained as a white amorphous solid (2.52 g, 2.98 mmol, 78% yield, MS/ESI+ 846.0 [MH]+).

Workup

  1. concentrationThen it was concentrated to about half volume
  2. additiondiluted with EtOAc (about 200 ml)
  3. washwashed with HCl 1N and NaHCO3 sat. sol. The organic layer
  4. dry with materialwas dried over Na2SO4
  5. customthe solvent was evaporated to dryness
  6. customThe crude (3.35 g) was purified by flash chromatography on silica gel (eluent: Et20/EtOAc 2/1)

Sources & evidence

ORD record
ord-1d8268cc22684535893d7e1f6c11aff6
Source dataset
uspto-grants-2016_02
Patent number
US09265768B2

Reaction notes

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