Potassium Phosphate, Tribasic → (S)-N-(7-(2-fluoropyridin-3-yl)-3-(neopentyloxy)-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,4]oxazine]-5'-yl)formamide

HRID 1472406Notes

Reaction equation

Br[C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH:21][CH:22]=[O:23])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12]([O:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:30][C:31]1[C:36](B(O)O)=[CH:35][CH:34]=[CH:33][N:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:30][C:31]1[C:36]([C:2]2[CH:3]=[C:4]3[C@:15]4([N:20]=[C:19]([NH:21][CH:22]=[O:23])[CH2:18][O:17][CH2:16]4)[C:14]4[CH:13]=[C:12]([O:24][CH2:25][C:26]([CH3:28])([CH3:29])[CH3:27])[N:11]=[CH:10][C:9]=4[O:8][C:5]3=[CH:6][CH:7]=2)=[CH:35][CH:34]=[CH:33][N:32]=1

Participants

Conditions

Temperature: 100 °C

Procedure

A vial was charged with neopentyl alcohol (0.579 g, 6.57 mmol) and DMF (6.57 mL). Sodium hydride (60% in mineral oil; 0.263 g, 6.57 mmol) was added and the reaction was stirred for 10 minutes at room temperature. The vial was heated to 100° C. for 5 min. The vial was cooled to rt. (S)-7-bromo-3-chloro-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.500 g, 1.314 mmol) was added in one portion. The vial was sealed and heated to 100° C. three hours. The mixture was diluted with ethyl acetate and water. A small amount of brine was added and the layers were separated. The aq. layer was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (0-100% EtOAc/Hexanes) to give 175 mg of (S)—N-(7-bromo-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazine]-5′-yl)formamide as a light yellow solid. Step 2: A microwave vial was charged with (S)—N-(7-bromo-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazine]-5′-yl)formamide (0.075 g, 0.163 mmol), 2-fluoropyridin-3-ylboronic acid (0.046 g, 0.326 mmol), potassium phosphate (0.104 g, 0.489 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5.77 mg, 8.15 μmol). The vial was flushed with Ar (g), then dioxane (0.611 mL) and water (0.204 mL) were added in sequence. The vial was sealed and heated in a Biotage Initiator microwave reactor for 30 min at 100° C. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (0-10% MeOH:DCM w/1% NH4OH) to afford 32 mg of (S)—N-(7-(2-fluoropyridin-3-yl)-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazine]-5′-yl)formamide as an off-white solid.

Workup

customThe vial was flushed with Ar (g)
additiondioxane (0.611 mL) and water (0.204 mL) were added in sequence
customThe vial was sealed
additionThe reaction was diluted with EtOAc
washwashed with water
extractionThe aqueous layer was extracted with EtOAc
washthe combined organic layers were washed with brine
dry with materialdried with sodium sulfate
filtrationfiltered
concentrationconcentrated
customThe material was purified via column chromatography (0-10% MeOH:DCM w/1% NH4OH)

Sources & evidence

ORD record: ord-b86aa186d1874ce3a0666d51238c6478
Source dataset: uspto-grants-2015_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09012446B2

Reaction notes

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