Pyridine → (S)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine

HRID 1523557Notes

Reaction equation

HRID 1523557 reaction equation
[N-:1]=[C:2]=[S:3].[Na+].N1C=CC=CC=1.CS(O[N:16]=[C:17](Cl)[C@H:18]1[CH2:22][O:21][C:20]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[O:19]1)(=O)=O.[CH3:29][C:30]1[C:35]([O:36][C:37]2[C:38]([NH2:50])=[N:39][CH:40]=[C:41]([S:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)[CH:42]=2)=[CH:34][CH:33]=[CH:32][N:31]=1>C(#N)C>[CH3:29][C:30]1[C:35]([O:36][C:37]2[C:38]([NH:50][C:2]3[S:3][N:16]=[C:17]([C@H:18]4[CH2:22][O:21][C:20]5([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]5)[O:19]4)[N:1]=3)=[N:39][CH:40]=[C:41]([S:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)[CH:42]=2)=[CH:34][CH:33]=[CH:32][N:31]=1

Participants

6

Reactant 4

HCID 1049PyridineHCID 10953423IsothiocyanatosodiumHCID 674857913-(2-Methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amineHCID 86644147(R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride

Product 1

HCID 67486135(S)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amineYield 70.3%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
60 °C

Procedure

To 700 mL of acetonitrile was added sodium isothiocyanate (12.5 g, 155 mmol), pyridine (25.2 ml, 309 mmol) and (R)—N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (38.4 g, 129 mmol) and the reaction heated to 60° C. for 15 minutes (white solid formed). To the mixture was added 3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (32 g, 103 mmol) as a solid and the reaction was stirred for 14 hours at 60° C. The reaction was cooled and concentrated in vacuo. The residue was partitioned between EtOAc and 1N NaOH. The aqueous mixture (basic, about 700 ML) was extracted twice with EtOAc (3000 mL total volume). The combined organic layers were washed with 1N NaOH (300 mL) and brine (300 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography on about 1 kg of silica gel using 1:1 EtOAc/CH2Cl2 with 1% MeOH as eluent to afford (S)—N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (38.7 g, 72.4 mmol, 70.2% yield).

Workup

  1. custom(white solid formed)
  2. temperatureThe reaction was cooled
  3. concentrationconcentrated in vacuo
  4. customThe residue was partitioned between EtOAc and 1N NaOH
  5. extractionThe aqueous mixture (basic, about 700 ML) was extracted twice with EtOAc (3000 mL total volume)
  6. washThe combined organic layers were washed with 1N NaOH (300 mL) and brine (300 mL)
  7. dry with materialdried over MgSO4
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified by chromatography on about 1 kg of silica gel using 1:1 EtOAc/CH2Cl2 with 1% MeOH as eluent

Sources & evidence

ORD record
ord-1205a05e33554ca787597ab281a1b949
Source dataset
uspto-grants-2015_07
Patent number
US09079890B2

Reaction notes

Loading…