Lawesson's reagent → (R)-5-[5-(3-chloro-6,7-dihydro-5H-[1]pyrindin-7-ylamino)-2-fluoro-phenyl]-6,6-difluoro-5-methyl-[1,4]oxazepane-3-thione

HRID 403240Notes

Reaction equation

HRID 403240 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][CH:8]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([F:29])=[C:16]([C@:18]4([CH3:28])[C:24]([F:26])([F:25])[CH2:23][O:22][CH2:21][C:20](=O)[NH:19]4)[CH:17]=3)[C:5]2=[N:6][CH:7]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:39]2)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[N:6][C:5]2[CH:8]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([F:29])=[C:16]([C@:18]4([CH3:28])[C:24]([F:26])([F:25])[CH2:23][O:22][CH2:21][C:20](=[S:39])[NH:19]4)[CH:17]=3)[CH2:9][CH2:10][C:4]=2[CH:3]=1

Participants

5

Reactant 3

HCID 87949Lawesson's reagentHCID 516892Sodium BicarbonateHCID 68226747(5R)-5-(5-(3-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylamino)-2-fluorophenyl)-6,6-difluoro-5-methyl-1,4-oxazepan-3-one

Product 1

HCID 88950947(R)-5-[5-(3-chloro-6,7-dihydro-5H-[1]pyrindin-7-ylamino)-2-fluoro-phenyl]-6,6-difluoro-5-methyl-[1,4]oxazepane-3-thioneYield 129%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of (5R)-5-(5-(3-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylamino)-2-fluorophenyl)-6,6-difluoro-5-methyl-1,4-oxazepan-3-one (intermediate A22A) (62 mg, 146 μmmol) in dioxane (2.2 ml) at 23° C. was added 2,4-bis-(4-methoxy-phenyl)-[1,3,2,4]dithiadiphosphetane 2,4-disulfide (Lawesson's reagent) (38.3 mg, 94.6 μmmol) and the mixture was stirred at 80° C. for 3 h. The reaction mixture was poured onto sat. NaHCO3-solution and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to give a yellow solid, which was purified by silica gel column chromatography with n-heptane/ethyl acetate to give the (R)-5-[5-(3-chloro-6,7-dihydro-5H-[1]pyrindin-7-ylamino)-2-fluoro-phenyl]-6,6-difluoro-5-methyl-[1,4]oxazepane-3-thione (54 mg, 84%) as a white solid. MS (ISP): m/z=443.0 [(M+H)+].

Workup

  1. extractionextracted twice with ethyl acetate
  2. washThe combined organic layers were washed with brine
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. customevaporated
  6. customto give a yellow solid, which
  7. customwas purified by silica gel column chromatography with n-heptane/ethyl acetate

Sources & evidence

ORD record
ord-ec3f6b2b058246fb8f2c341ac30d1e6f
Source dataset
uspto-grants-2014_06
Patent number
US08748418B2

Reaction notes

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