Sodium hydride → HCID 67485792, compound
Reaction equation
[CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[C:12]1[CH:13]=[C:14]([N+]([O-])=O)[C:15]([C:18]#[N:19])=[N:16][CH:17]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29]>CN(C=O)C>[CH3:1][C:2]1[C:7]([O:8][C:14]2[C:15]([C:18]#[N:19])=[N:16][CH:17]=[C:12]([S:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1Participants
Conditions
- Temperature
- 2 °C
Procedure
To 600 mL of DMF in a 4neck 3000 mL round bottom flask equipped with an overhead stir mechanism under nitrogen was added 2-methylpyridin-3-ol (71.8 g, 658 mmol), and the reaction was cooled to 2° C. 60% sodium hydride (26.3 g, 658 mmol) was added over 30 minutes while maintaining the internal temperature below 10° C. The reaction was stirred while warming to ambient temperature for 1 hour. To the reaction was added 5-bromo-3-nitropicolinonitrile (150 g, 658 mmol) in a solution of 400 mL of DMF in two portions and the reaction held at ambient temperature for 1.5 hours. Pyridine-2-thiol (73.1 g, 658 mmol) was added as a solid in portions at ambient temperature and the reaction was stirred for 15 minutes to dissolve the material. The reaction was cooled to 3° C. and sodium hydride (26.3 g, 658 mmol) again was added in portions over about 35 minutes while maintaining the reaction temperature below 10° C. The reaction was removed from the ice bath and warmed to ambient temperature while stirring for 12 hours. The reaction was diluted with 4 volumes (8 L) of brine and stirred for 30 minutes, at which point solid formed. The solid was removed by filtration and the filtrate was extracted with MTBE (10 L total). The MTBE phase was concentrated in vacuo. The solid was combined with concentrated material and dissolved in ethyl acetate (3 L). The EtOAc was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The solid that formed was ground into a powder and dried in vacuo for 4 hours. The material was taken up in 30 mL of MTBE/10 g of product and the reaction was stirred for 30 minutes. The solid was filtered and dried in vacuo (2 hours). The mother liquor was concentrated and triturated again with MTBE (same dilution rate). The solids were combined and dried for 3 hours in vacuo to yield 3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (181 g, 85%)
Workup
- temperaturewhile maintaining the internal temperature below 10° C
- stirringThe reaction was stirred
- temperaturewhile warming to ambient temperature for 1 hour
- stirringthe reaction was stirred for 15 minutes
- dissolutionto dissolve the material
- temperatureThe reaction was cooled to 3° C.
- temperaturewhile maintaining the reaction temperature below 10° C
- customThe reaction was removed from the ice bath
- temperaturewarmed to ambient temperature
- stirringwhile stirring for 12 hours
- additionThe reaction was diluted with 4 volumes (8 L) of brine
- stirringstirred for 30 minutes, at which point solid
- customformed
- customThe solid was removed by filtration
- extractionthe filtrate was extracted with MTBE (10 L total)
- concentrationThe MTBE phase was concentrated in vacuo
- dissolutiondissolved in ethyl acetate (3 L)
- washThe EtOAc was washed with brine
- dry with materialdried over MgSO4
- filtrationfiltered
- concentrationconcentrated in vacuo
- customThe solid that formed
- customdried in vacuo for 4 hours
- stirringthe reaction was stirred for 30 minutes
- filtrationThe solid was filtered
- customdried in vacuo (2 hours)
- concentrationThe mother liquor was concentrated
- customtriturated again with MTBE (same dilution rate)
- customdried for 3 hours in vacuo
Sources & evidence
- ORD record
- ord-74faf55169c24f559da36ba738b4e579
- Source dataset
- uspto-grants-2014_10
- Patent number
- US08853409B2
Reaction notes
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