Sodium t-butoxide → HCID 178517870, compound
Reaction equation
Cl[C:2]1[C:7]([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:23][C@H:24]1[CH2:27][C@H:26](N)[CH2:25]1.CC(C)([O-:32])C.[Na+]>[Pd](Cl)Cl>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:23][C@H:24]1[CH2:27][C@H:26]([N:13]2[C:2]3=[N:3][CH:4]=[CH:5][CH:6]=[C:7]3[C:8]3([CH2:11][CH2:10][CH2:9]3)[C:12]2=[O:32])[CH2:25]1Participants
Conditions
- Temperature
- 90 °C
Procedure
1-(2-Chloropyridin-3-yl)cyclobutanecarbonitrile (intermediate 19, 0.070 g, 0.363 mmol), (trans)-N1-(benzo[d]thiazol-2-yl)cyclobutane-1,3-diamine (intermediate 11, 0.080 g, 0.363 mmol), [dicyclohexyl(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine]2-(2-aminoethyl)phenyl)palladium(II) chloride (0.015 g, 0.018 mmol), and sodium t-butoxide (0.096 ml, 0.780 mmol) were combined under argon in a ROUND BOTTOMED FLASK. Dry, sparged dioxane (0.8 mL) was added and the reaction heated at 90° C. After 25 minutes water (150 mL), saturated ammonium chloride (20 mL) and ethyl acetate (200 mL) were added and the phases mixed and separated. The organic phase was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude intermediate was dissolved in a mixture of water (5 mL) and concentrated sulfuric acid (5 mL) and heated at 100° C. After 5 hours the reaction was allowed to cool to room temperature. Water (100 mL) and ethyl acetate (100 mL) were added and the phases mixed and separated. The organic phase was discarded. Ice (100 mL) was added to the aqueous along with additional ethyl acetate (200 mL). The pH was adjusted to about 9 using 10 N sodium hydroxide and the phases mixed and separated. The aqueous was extracted with an additional portion of ethyl acetate (100 mL) then the combined organics were dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (dichloromethane to ethyl acetate gradient) gave the desired 1′-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)spiro[cyclobutane-1,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (0.041 g, 0.109 mmol, 30.0% yield). M+1: 377.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.17-2.55 (m, 6 H) 2.61-2.78 (m, 2 H) 3.42-3.58 (m, 2 H) 4.53-4.67 (m, 1 H) 5.29 (quin, J=8.46 Hz, 1 H) 6.38 (br. s., 1 H) 6.99 (dd, J=7.24, 5.28 Hz, 1 H) 7.08 (td, J=7.58, 1.08 Hz, 1 H) 7.24-7.33 (m, 1 H) 7.54-7.64 (m, 2 H) 7.70 (dd, 1=7.24, 1.56 Hz, 1 H) 8.17 (dd, J=5.28, 1.56 Hz, 1 H).
Workup
- customDry
- customsparged dioxane (0.8 mL)
- additionwas added
- additionAfter 25 minutes water (150 mL), saturated ammonium chloride (20 mL) and ethyl acetate (200 mL) were added
- additionthe phases mixed
- customseparated
- dry with materialThe organic phase was dried with magnesium sulfate
- customevaporated to dryness under reduced pressure
- dissolutionThe crude intermediate was dissolved in a mixture of water (5 mL) and concentrated sulfuric acid (5 mL)
- temperatureheated at 100° C
- temperatureto cool to room temperature
- additionWater (100 mL) and ethyl acetate (100 mL) were added
- additionthe phases mixed
- customseparated
- additionIce (100 mL) was added to the aqueous along with additional ethyl acetate (200 mL)
- additionthe phases mixed
- customseparated
- extractionThe aqueous was extracted with an additional portion of ethyl acetate (100 mL)
- dry with materialthe combined organics were dried with magnesium sulfate
- customevaporated to dryness under reduced pressure
- customPurification
Sources & evidence
- ORD record
- ord-031485cba1df4e0eb962c79ea01e1ed4
- Source dataset
- uspto-grants-2015_11
- Patent number
- US09174992B2
Reaction notes
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