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

HRID 1172387Notes

Reaction equation

C(O[C:4](=[O:22])[C:5]([CH2:12][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)([CH3:11])[CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])C.[CH3:23][S:24]([NH:27][C:28]1[CH:43]=[CH:42][C:31]2[NH:32][C:33]([CH2:38][C:39](O)=[O:40])=[N:34][S:35](=[O:37])(=[O:36])[C:30]=2[CH:29]=1)(=[O:26])=[O:25].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[H-].[Na+]>CN(C)C=O>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:13]2[CH2:12][C:5]([CH3:11])([CH2:6][CH2:7][CH:8]([CH3:9])[CH3:10])[C:4]([OH:22])=[C:38]([C:33]3[NH:32][C:31]4[CH:42]=[CH:43][C:28]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:29][C:30]=4[S:35](=[O:36])(=[O:37])[N:34]=3)[C:39]2=[O:40])=[CH:20][CH:19]=1

Participants

Conditions

Temperature: 25 °C

Procedure

A solution of 2-[(4-fluoro-benzylamino)-methyl]-2,5-dimethyl-hexanoic acid ethyl ester (93 mg, 0.30 mmol), (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (100 mg, 0.30 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60 mg, 0.315 mmol) in anhydrous N,N-dimethyformamide (4 mL) was treated with N-methyl morpholine (0.069 mL, 0.63 mmol). The reaction was stirred under a nitrogen environment at 25° C. for 1 h, quenched with a 1.0 M aqueous hydrochloric acid solution (50 mL), extracted with ethyl acetate (2×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was dissolved in ethanol (5 mL) and treated with a 60% oil dispersion of sodium hydride (48 mg, 2.0 mmol). The reaction was heated at 60° C. under a nitrogen environment for 1.5 h. The reaction mixture was allowed to cool to 25° C., quenched with a 0.5 M aqueous hydrochloric acid solution (50 mL), extracted with ethyl acetate (2×50 mL), washed with brine (50 mL), dried with sodium sulfate, filtered, and concentrated in vacuo. The crude resin was purified by flash column chromatography (ISCO RediSep column, 0 to 100% ethyl acetate in hexanes) to afford the desired product, N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-5-methyl-5-(3-methyl-butyl)-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 (67 mg, 38%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 0.81 (t, 6H, J=7.0 Hz), 0.87-1.04 (m, 3H), 1.14 (s, 3H), 1.23-1.56 (m, 4H), 3.06 (s, 3H), 3.15 (q, 2H, J=11.4 Hz), 4.62 (dd, 2H, J1=115.3 Hz, J2=14.7, Hz), 7.03-7.10 (m, 2H), 7.18-7.30 (m, 3H), 7.62-7.71 (m, 2H). LC-MS (ESI) calculated for C26H31FN4O6S2: 578.6, found 579.2 [M+H+].

Workup

customquenched with a 1.0 M aqueous hydrochloric acid solution (50 mL)
extractionextracted with ethyl acetate (2×50 mL)
dry with materialdried over sodium sulfate
filtrationfiltered
concentrationconcentrated in vacuo
dissolutionThe resulting oil was dissolved in ethanol (5 mL)
temperatureThe reaction was heated at 60° C. under a nitrogen environment for 1.5 h
temperatureto cool to 25° C.
customquenched with a 0.5 M aqueous hydrochloric acid solution (50 mL)
extractionextracted with ethyl acetate (2×50 mL)
washwashed with brine (50 mL)
dry with materialdried with sodium sulfate
filtrationfiltered
concentrationconcentrated in vacuo
customThe crude resin was purified by flash column chromatography (ISCO RediSep column, 0 to 100% ethyl acetate in hexanes)

Sources & evidence

ORD record: ord-211982c9f996416db4d7569b7897dff1
Source dataset: uspto-grants-2010_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07834009B2

Reaction notes

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