Hydrochloric Acid → (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3-(cyclopropylmethoxy)-4-(methylsulfonamido)-benzyloxy)carbonyloxy)ethyl)pyridine 1-oxide

HRID 1776637Notes

Reaction equation

HRID 1776637 reaction equation
[Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:10][C:11]([O:13]C1C=CC([N+]([O-])=O)=CC=1)=[O:12].[CH:40]1([CH2:43][O:44][C:45]2[CH:50]=[C:49]([CH2:51]O)[CH:48]=[CH:47][C:46]=2[N:53]([S:61]([CH3:64])(=[O:63])=[O:62])C(=O)OC(C)(C)C)[CH2:42][CH2:41]1.Cl.O1CCOCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:10][C:11]([O:13][CH2:51][C:49]1[CH:48]=[CH:47][C:46]([NH:53][S:61]([CH3:64])(=[O:63])=[O:62])=[C:45]([O:44][CH2:43][CH:40]2[CH2:42][CH2:41]2)[CH:50]=1)=[O:12]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 86679418(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-nitrophenoxy)-carbonyloxy)ethyl)pyridine 1-oxideHCID 86679440Tert-butyl 2-(cyclopropylmethoxy)-4-(hydroxymethyl)phenyl(methylsulfonyl)carbamate

Product 1

HCID 71542817(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3-(cyclopropylmethoxy)-4-(methylsulfonamido)-benzyloxy)carbonyloxy)ethyl)pyridine 1-oxideYield 39.7%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent

Procedure

To a stirred solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-nitrophenoxy)carbonyloxy)ethyl)pyridine 1-oxide (prepared in an analogous manner as described in Scheme 3, Step 1) (0.150 g, 0.256 mmol) in DCM (10 ml), DMAP (0.0156 g, 0.128 mmol) was added followed by tert-butyl 2-(cyclopropylmethoxy)-4-(hydroxymethyl)phenyl(methylsulfonyl)carbamate (0.124 g, 0.333 mmol), and the resulting mixture was stirred at RT for 3 hours. HCl 4M in dioxane (3 ml, 12 mmol) was added and the reaction was stirred at RT for additional 5 hours. The solvent was removed under vacuum and the residue was purified by flash chromatography on silica gel column (DCM:MeOH=10:0.15). A further purification by flash chromatography on silica gel column (DCM:acetone=10:1) was required to obtain (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3-(cyclopropylmethoxy)-4-(methylsulfonamido)-benzyloxy)carbonyloxy)ethyl)pyridine 1-oxide as a white solid (0.073 g, 0.102 mmol, 39.7% yield, MS/ESI+ 716.93 [MH]+, [αD]=−11.84, c=0.495, DCM).

Workup

  1. stirringthe reaction was stirred at RT for additional 5 hours
  2. customThe solvent was removed under vacuum
  3. customthe residue was purified by flash chromatography on silica gel column (DCM:MeOH=10:0.15)
  4. customA further purification by flash chromatography on silica gel column (DCM:acetone=10:1)

Sources & evidence

ORD record
ord-a640043a1c4c4fd1986a84f6bd090a67
Source dataset
uspto-grants-2016_02
Patent number
US09265768B2

Reaction notes

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