Nitric Acid → (4aS,5S,7aS)-7a-(2,3-difluoro-5-nitrophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine

HRID 1429622Notes

Reaction equation

[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([C:18]([F:21])([F:20])[F:19])[C@H:14]1[CH2:13][S:12][C:11]([NH2:22])=[N:10]2.S(=O)(=O)(O)O.[N+:28]([O-])([OH:30])=[O:29].[OH-].[Na+]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:28]([O-:30])=[O:29])=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([C:18]([F:19])([F:21])[F:20])[C@H:14]1[CH2:13][S:12][C:11]([NH2:22])=[N:10]2

Participants

Conditions

Temperature: 0 °C

Procedure

(4aS,5S,7aS)-7a-(2,3-Difluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (1.42 g) was dissolved in TFA (6 mL), and the solution was cooled to 0° C. Sulfuric acid (conc., 1 mL) was added, followed by fuming nitric acid (0.30 mL) dropwise over 20 mins. After stirring at 0° C. for 1 h, the reaction mixture was poured onto ice (50 g) and basified to pH 12 with 2 N NaOH (aq.). After allowing the ice to melt, the mixture was extracted with EtOAc (3×75 mL), and the combined organic portions dried over MgSO4 and evaporated to afford the title compound (1.91 g, purity approx. 80%) which was used in the subsequent step without purification. 1H NMR (400 MHz, CDCl3) δ ppm 2.88 (dd, J=13.8, 3.9 Hz, 1 H), 3.11 (dd, J=13.6, 2.8 Hz, 1 H), 3.37 (dt, J=7.4, 3.5 Hz, 1 H), 3.93 (d, J=7.8 Hz, 1 H), 4.53-4.83 (m, 4 H), 8.09 (ddd, J=9.0, 6.3, 2.9 Hz, 1 H), 8.27 (dt, J=5.2, 2.6 Hz, 1 H)

Workup

additionthe reaction mixture was poured onto ice (50 g)
extractionthe mixture was extracted with EtOAc (3×75 mL)
dry with materialthe combined organic portions dried over MgSO4
customevaporated

Sources & evidence

ORD record: ord-d5bfddd0e2a94697aa449660286b3fd7
Source dataset: uspto-grants-2015_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08940734B2

Reaction notes

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