4-Methylmorpholine → N-[3-[1-[(4-fluorophenyl)methyl]-4-hydroxy-3-(3-methylbut-2-enyl)-6-oxo-2,3-dihydropyridin-5-yl]-1,1-dioxo-4H-1$l^{6},2,4-benzothiadiazin-7-yl]methanesulfonamide

HRID 1172382Notes

Reaction equation

C(O[C:4](=[O:21])[CH:5]([CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])C.[CH3:22][S:23]([NH:26][C:27]1[CH:42]=[CH:41][C:30]2[NH:31][C:32]([CH2:37][C:38](O)=[O:39])=[N:33][S:34](=[O:36])(=[O:35])[C:29]=2[CH:28]=1)(=[O:25])=[O:24].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[H-].[Na+]>CN(C)C=O.Cl>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:12]2[CH2:11][CH:5]([CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])[C:4]([OH:21])=[C:37]([C:32]3[NH:31][C:30]4[CH:41]=[CH:42][C:27]([NH:26][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:28][C:29]=4[S:34](=[O:35])(=[O:36])[N:33]=3)[C:38]2=[O:39])=[CH:19][CH:18]=1

Participants

Conditions

Temperature: 25 °C

Procedure

A solution of 2-[(4-fluoro-benzylamino)-methyl]-5-methyl-hex-4-enoic acid ethyl ester (102 mg, 0.35 mmol), (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (115 mg, 0.345 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (69 mg, 0.36 mmol) in anhydrous N,N-dimethylformamide (5 mL) was treated with N-methylmorpholine. The reaction was stirred for 1 h at 25° C., diluted with a 1.0 M aqueous hydrochloric acid solution (20 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in ethanol (6 mL) and treated with a 60% oil dispersion of sodium hydride (41 mg, 1.74 mmol). The reaction was heated at 70° C. for 1 h, allowed to cool to 25° C., and quenched with a 1.0 M aqueous hydrochloric acid solution (50 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL), and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude oil was purified by flash column chromatography (ISCO RediSep column, 10 to 80% ethyl acetate in hexanes) to give N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-5-(3-methyl-but-2-enyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (90 mg, 46%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ: 1.54 (s, 3H), 1.69 (s, 3H), 2.15-2.23 (m, 1H), 2.39-2.44 (m, 1H), 2.60-2.66 (m, 1H), 3.06 (s, 3H), 3.19 (dd, 1H, J1=13.1 Hz, J2=4.3 Hz), 3.45 (dd, 1H, J1=12.4 Hz, J2=5.4 Hz), 4.61 (s, 2H), 4.89 (t, 3H, J=6.6 Hz), 7.05 (t, 2H, J=8.5 Hz), 7.23-7.28 (m, 3H), 7.63-7.66 (m, 1H), 7.69 (d, 1H, J=2.2 Hz). LC-MS (ESI) calculated for C25H27FN4O6S2: 562.6, found 563.4 [M+H+].

Workup

extractionextracted with ethyl acetate (3×50 mL)
dry with materialThe combined organic layers were dried over magnesium sulfate
filtrationfiltered
concentrationconcentrated in vacuo
dissolutionThe residue was dissolved in ethanol (6 mL)
temperatureThe reaction was heated at 70° C. for 1 h
temperatureto cool to 25° C.
customquenched with a 1.0 M aqueous hydrochloric acid solution (50 mL)
extractionThe resulting mixture was extracted with ethyl acetate (3×50 mL)
dry with materialthe combined organic layers were dried over magnesium sulfate
filtrationfiltered
concentrationconcentrated in vacuo
customThe crude oil was purified by flash column chromatography (ISCO RediSep column, 10 to 80% ethyl acetate in hexanes)

Sources & evidence

ORD record: ord-91e7310a7d4c4271a325f57ada2de897
Source dataset: uspto-grants-2010_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07834009B2

Reaction notes

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