1,4-Dioxane → HCID 71543110, compound

HRID 1776509Notes

Reaction equation

HRID 1776509 reaction equation
C(OC([N:8]([C:13]1[CH:51]=[CH:50][C:16]([CH2:17][N:18]([CH3:49])[CH2:19][C:20]([O:22][C@H:23]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]3[CH2:48][CH2:47]3)[CH:35]=2)[CH2:24][C:25]2[C:30]([Cl:31])=[CH:29][N+:28]([O-:32])=[CH:27][C:26]=2[Cl:33])=[O:21])=[CH:15][CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.O1CCOCC1.C([O-])(O)=O.[Na+]>C(Cl)Cl.Cl>[Cl:33][C:26]1[CH:27]=[N+:28]([O-:32])[CH:29]=[C:30]([Cl:31])[C:25]=1[CH2:24][C@@H:23]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:42])[F:43])=[C:36]([O:44][CH2:45][CH:46]2[CH2:47][CH2:48]2)[CH:35]=1)[O:22][C:20](=[O:21])[CH2:19][N:18]([CH3:49])[CH2:17][C:16]1[CH:15]=[CH:14][C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:51][CH:50]=1

Participants

6

Reactant 3

HCID 312751,4-DioxaneHCID 516892Sodium BicarbonateHCID 89455885HCID 89455885, compound

Product 1

HCID 71543110HCID 71543110, compound

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 6344DichloromethaneSolvent2×

Procedure

To a solution of (S)-4-(2-(2-((4-(N-(tert-butoxycarbonyl)methylsulfonamido)benzyl)(methyl)amino)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.250 g, 0.323 mmol) in DCM (15 ml), HCl 4M in dioxane (2 ml, 8.00 mmol) was added, and the solution was stirred at RT overnight. The mixture was portioned between DCM and 5% NaHCO3, and the organic layer was dried over sodium sulfate. The solvent was removed, and the crude was purified by flash chromatography on silica gel cartridge (DCM:MeOH=99:1 to 97:3) to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(methyl(4-(methylsulfonamido)benzyl)amino)-acetoxy)ethyl)pyridine 1-oxide, free base (0.120 g, 0.178 mmol, 55.1% yield), as a colorless amorphous solid. This product was dissolved in DCM (12 ml) and HCl 4M in dioxane (0.089 ml, 0.356 mmol) was added; the mixture was stirred at RT for 2 hours, and volatiles were removed under vacuum. The product was further dissolved in DCM and washed with 5% NaHCO3. The organic phase was dried over Na2SO4, and the crude was purified by chromatography on silica gel cartridge (DCM/EtOAc 90/10 to EtOAc 100%) followed by a further filtration through a silica gel cartridge (DCM/MeOH 99/1 to 98/2) to give 0.090 g of free base. This product was dissolved in 5 ml of DCM, and HCl 4M in dioxane (0.044 ml, 0.177 mmol) was added. The mixture was stirred at RT for 1 hour. The solvent was removed to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(methyl-(4-(methylsulfonamido)benzyl)amino)acetoxy)ethyl)pyridine 1-oxide hydrochloride (0.095 g, 0.134 mmol, 41.5% yield, MS/ESI+ 673.99 [MH]+)

Workup

  1. dry with materialthe organic layer was dried over sodium sulfate
  2. customThe solvent was removed
  3. customthe crude was purified by flash chromatography on silica gel cartridge (DCM:MeOH=99:1 to 97:3)

Sources & evidence

ORD record
ord-d7443f7e7cfc4d4e95ab2828557e17b5
Source dataset
uspto-grants-2016_02
Patent number
US09265768B2

Reaction notes

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