Potassium Phosphate, Tribasic → HCID 68292442, compound

HRID 1507961Notes

Reaction equation

Br[C:2]1[CH:3]=[C:4]2[C:9]([S:10][CH2:11][CH3:12])=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=[N:6][N:5]2[CH:16]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:3]=[C:4]3[C:9]([S:10][CH2:11][CH3:12])=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=[N:6][N:5]3[CH:16]=2)=[CH:21][CH:20]=1)#[N:18]

Participants

Conditions

Temperature: 125 °C

Procedure

A mixture of 6-bromo-4-(ethylthio)pyrrolo[1,2-b]pyridazine-3-carboxamide (1.2 g, 4.00 mmol), 4-cyanophenylboronic acid (0.881 g, 6.00 mmol), palladium (II) acetate (0.090 g, 0.400 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbyphenyl (XPhos) (0.381 g, 0.800 mmol) was pumped under vacuum and backfilled with nitrogen three times. Next, potassium phosphate, tribasic, 2M (7.60 mL, 15.19 mmol) and dioxane (Volume: 30 mL) were quickly added. The resulting orange suspension was again pumped under vacuum and backfilled with nitrogen three times. The reaction vessel was sealed and heated behind a blast shield in a 125° C. oil bath for 4 h. LCMS and HPLC showed that the desired product was formed, but the reaction was incomplete. The mixture was cooled to room temperature and 4-cyanophenylboronic acid (0.366 g, 3.00 mmol), palladium (II) acetate (0.045 g, 0.200 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.191 g, 0.400 mmol) were added. The resulting mixture was again pumped under vacuum and backfilled with nitrogen three times. The reaction vessel was sealed and heated behind a blast shield in a 125° C. oil bath for 1.5 h. The reaction mixture was partitioned between EtOAc (250 ml) and water (250 ml). The two phases were separated. The aqueous phase was extracted with EtOAc (2×50 mL). The combined organic phase was washed with brine (100 mL), dried (MgSO4) and concentrated to give a yellow solid. The solid residue was treated with Et2O (50 mL), stirred for 30 min, filtered, and washed with 1:1 mixture of Et2O-hexanes (2×15 mL) to give a yellow solid (889 mg). 1H NMR, HPLC and LCMS showed that the main component was the desired product, but the material was impure. The filtrate was found to contain a minor amount of the desired product. The impure material was treated with Et2O (50 mL), stirred for 30 min, filtered, washed with 1:1 mixture of Et2O-hexanes (2×15 mL) to give the title compound as yellow solid (787 mg). 1H NMR showed some improvement, but the material was still impure. The mixture was taken to the next reaction without purification.

Workup

customThe reaction vessel was sealed

Sources & evidence

ORD record: ord-e1f33ad9ee8d4f5d833c0551b4f5c6ff
Source dataset: uspto-grants-2015_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09221826B2

Reaction notes

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