1,8-Diazabicyclo(5.4.0)undec-7-ene → N-(6-((4R,6S)-2-amino-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-chloropicolinamide

HRID 930362Notes

Reaction equation

C([NH:9][C:10]1[O:11][C@H:12]([C:36]([F:39])([F:38])[F:37])[CH2:13][C@@:14]([C:19]2[N:24]=[C:23]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=3)[CH:22]=[CH:21][C:20]=2[F:35])([CH:16]([F:18])[F:17])[N:15]=1)(=O)C1C=CC=CC=1.N12CCCN=C1CCCCC2>CO>[NH2:9][C:10]1[O:11][C@H:12]([C:36]([F:37])([F:39])[F:38])[CH2:13][C@@:14]([C:19]2[N:24]=[C:23]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=3)[CH:22]=[CH:21][C:20]=2[F:35])([CH:16]([F:17])[F:18])[N:15]=1

Participants

Conditions

Temperature: 80 °C

Procedure

To a solution of N-(6-((4R,6S)-2-benzamido-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-chloropicolinamide (16 mg, 0.028 mmol) in MeOH (74.60 in a flask was added 1,8-diazabicyclo-[5.4.0]undec-7-ene (336 μl, 2.249 mmol). The vial was sealed and was heated at 80° C. for 4 h. The reaction was diluted with MeOH and purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 70% over 16 min, then neutralized with solid NaHCO3 and extracted with DCM to provide N-(6-((4R,6S)-2-amino-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-chloropicolinamide (1.8 mg, 3.85 μmol, 13.75% yield) as a off-white solid. MS m/z=467, 469 M+; Calculated for C17H12ClF6N5O2: 467.75.

Workup

customThe vial was sealed
custompurified by reverse-phase preparative HPLC
customover 16 min
extractionextracted with DCM

Sources & evidence

ORD record: ord-3a6d43d3ab524cf492e7010295fa35c4
Source dataset: uspto-grants-2016_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09296734B2

Reaction notes

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