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 4 neck 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 cooled to 2° C. 60% sodium hydride (26.3 g, 658 mmol) was added at such a rate that the internal temperature did not exceed 10° C. over a period of 30 minutes. 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. To the reaction at ambient temperature was added pyridine-2-thiol (73.1 g, 658 mmol) as a solid in portions 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 such that the internal temp did not go above 10° C. (35 minute addition time). 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. The mixture was stirred for 30 minutes, at which point solid formed. The solid was filtered off and filtrate 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 (4×1 L), 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 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
- stirringThe reaction was stirred
- temperaturewhile warming to ambient temperature for 1 hour
- waitthe reaction held at ambient temperature for 1.5 hours
- customTo the reaction at ambient temperature
- stirringthe reaction was stirred for 15 minutes
- dissolutionto dissolve the material
- temperatureThe reaction was cooled to 3° C.
- customdid not go above 10° C.
- addition(35 minute addition time)
- 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
- stirringThe mixture was stirred for 30 minutes, at which point solid
- customformed
- filtrationThe solid was filtered off
- extractionfiltrate 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 (4×1 L)
- 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 with MTBE (same dilution rate)
- customdried for 3 hours in vacuo
Sources & evidence
- ORD record
- ord-762891f940ce48cdb317a9801cc83de7
- Source dataset
- uspto-grants-2014_10
- Patent number
- US08853409B2
Reaction notes
Loading…