Phosphorus oxychloride → Auglurant

HRID 1525840Notes

Reaction equation

[CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[F:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:8](=[O:10])[C:6]2[CH:5]=[C:4]([O:11][C:12]3[CH:13]=[N:14][CH:15]=[N:16][CH:17]=3)[CH:3]=[C:2]([CH3:1])[N:7]=2)=[N:23][CH:24]=1

Participants

Conditions

Temperature: -15 °C

Procedure

6-methyl-4-(pyrimidin-5-yloxy)picolinic acid (610 mg, 2.64 mmol, 1 eq) and 5-fluoro-2-aminopyridine (296 mg, 2.64 mmol, 1 eq) were dissolved in pyridine (40 mL) in a flame-dried round-bottom flask. The reaction was cooled to −15° C. and phosphorus oxychloride (270 μL, 2.90 mmol, 1.1 eq) was added dropwise while keeping the temperature below −15° C. After stirring for 30 minutes at −15° C. and the reaction was quenched with ice-water and neutralized with 10% K2CO3. The mixture was extracted with EtOAc (3×) and the combined organics were dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 310 mg (36%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.18 (s, 1H), 8.88 (s, 2H), 8.40 (d, J=3.0 Hz, 1H), 8.27 (dd, J=9.2 Hz, 4.10 Hz, 1H), 7.86 (td, J=8.6, 3.1 Hz, 1H), 7.55 (d, J=2.3 Hz, 1H), 7.29 (d, J=2.3 Hz, 1H), 2.58 (s, 3H); ES-MS [M+1]+: 326.2.

Workup

customthe temperature below −15° C
customthe reaction was quenched with ice-water and neutralized with 10% K2CO3
extractionThe mixture was extracted with EtOAc (3×)
dry with materialthe combined organics were dried (MgSO4)
filtrationfiltered
concentrationconcentrated in vacuo
customPurification by flash chromatography on silica gel

Sources & evidence

ORD record: ord-870e55ed4c774a95acc533a52954fbdf
Source dataset: uspto-grants-2015_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09085562B2

Reaction notes

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