Sodium Bicarbonate → HCID 86673718, compound
Reaction equation
[CH:1]([C:3]1[C:8](I)=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]=[C:13]([C:15]#[N:16])[C:12]([I:17])=[N:11]1)=[O:2].[C:18]([C:22]1[CH:23]=[C:24]2[C:29](=[C:30]([F:32])[CH:31]=1)[C:28](=[O:33])[NH:27][N:26]=[CH:25]2)([CH3:21])([CH3:20])[CH3:19].C(=O)(O)[O-].[Na+]>CS(C)=O.[Cu](I)I>[C:18]([C:22]1[CH:23]=[C:24]2[C:29](=[C:30]([F:32])[CH:31]=1)[C:28](=[O:33])[N:27]([C:8]1[C:3]([CH:1]=[O:2])=[C:4]([N:10]3[CH:14]=[C:13]([C:15]#[N:16])[C:12]([I:17])=[N:11]3)[CH:5]=[CH:6][CH:7]=1)[N:26]=[CH:25]2)([CH3:21])([CH3:19])[CH3:20]Participants
Conditions
- Temperature
- 60 °C
Procedure
A oven dried flask was charged with 1-(2-formyl-3-iodo-phenyl)-3-iodo-1H-pyrazole-4-carbonitrile (1.703 g, 3.79 mmol), 6-tert-butyl-8-fluorophthalazin-1(2H)-one [prepared according to US2010/0222325] (919 mg, 4.17 mmol) and sodium bicarbonate (637 mg, 7.59 mmol) and taken up in dry dimethyl sulfoxide (30 ml). The mixture was degassed with argon in a sonication bath. Copper iodide (722 mg, 3.79 mmol) was added and the material was again degassed thoroughly. With sonication the mixture was heated to 60° C. for 2.5 hours and left at ambient overnight. Additional copper iodide (360 mg) was added and the material was heated for 4 hours at 60° C. under sonication. The flask was cooled to ambient and methylene chloride (40 ml) and water (40 ml) were added, with vigorous stirring. After 5 minutes the material was filtered through a plug of celite, rinsing well with a solution of 1% methanol in methylene chloride. The filtrate was transferred to a separatory funnel and the organic phase was collected. This was shaken with a 50% diluted brine solution (60 ml, some ragging). The methylene chloride phase was collected and the aqueous phases were back extracted with methylene chloride (note: some ragging observed. It helps to use larger volumes of organic and aqueous solutions on back extraction). The combined organic phase was dried with magnesium sulfate, filtered and stripped. The remainder was taken up in methylene chloride and purified through Analogix flash column chromatography eluting first with 100% dichloromethane (hold for 5 minutes) and then switch to a gradient of 1% to 3% methanol in dichloromethane (25 g silica gel) providing the desired 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-formyl-phenyl]-3-iodo-1H-pyrazole-4-carbonitrile as a light brown powder (1.2 g). LC/MS calc'd for C23H17FIN5O2 (m/e) 541.32, obs'd 542 (M+H, ES+).
Workup
- customA oven dried flask
- customThe mixture was degassed with argon in a sonication bath
- customthe material was again degassed thoroughly
- customWith sonication the mixture
- additionAdditional copper iodide (360 mg) was added
- temperaturethe material was heated for 4 hours at 60° C. under sonication
- temperatureThe flask was cooled to ambient and methylene chloride (40 ml) and water (40 ml)
- additionwere added, with vigorous stirring
- filtrationAfter 5 minutes the material was filtered through a plug of celite
- washrinsing well with a solution of 1% methanol in methylene chloride
- customThe filtrate was transferred to a separatory funnel
- customthe organic phase was collected
- customThe methylene chloride phase was collected
- extractionthe aqueous phases were back extracted with methylene chloride (note
- extractionon back extraction)
- dry with materialThe combined organic phase was dried with magnesium sulfate
- filtrationfiltered
- custompurified through Analogix flash column chromatography
- washeluting first with 100% dichloromethane (hold for 5 minutes)
Sources & evidence
- ORD record
- ord-18bb6eb32efc4125b5c299fe5fd1e756
- Source dataset
- uspto-grants-2014_05
- Patent number
- US08729078B2
Reaction notes
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