Ethanol → N-[3-[10-[(4-fluorophenyl)methyl]-7-hydroxy-9-oxo-10-azaspiro[4.5]dec-7-en-8-yl]-1,1-dioxo-4H-1$l^{6},2,4-benzothiadiazin-7-yl]methanesulfonamide

HRID 1172392Notes

Reaction equation

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

Participants

Conditions

Temperature: 25 °C

Procedure

A solution of [1-(4-fluoro-benzylamino)-cyclopentyl]-acetic acid methyl ester (109 mg, 0.41 mmol) and (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (150 mg, 0.45 mmol) in anhydrous N,N-dimethylformamide (4 mL) was treated sequentially with N-methylmorpholine (100 μL, 0.91 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol). The reaction mixture was stirred at 25° C. for 1 h, diluted with a 1.0 M aqueous hydrochloric acid solution (20 mL), and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in ethanol (5 mL), treated with a 21 wt % solution of sodium ethoxide in ethanol (1.0 mL, 2.73 mmol). The reaction was stirred and heated at 60° C. for 1.5 h, allowed to cool to 25° C., and quenched with a 0.5 M aqueous hydrochloric acid solution (10 mL). The resulting mixture was extracted with ethyl acetate (3×40 mL) and the combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by prep-HPLC [Column Luna 5μ C18(2) 100 Å AXIA 150×21.2 mm, 5 micron, 30-100% in7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, N-{3-[6-(4-fluoro-benzyl)-9-hydroxy-7-oxo-6-aza-spiro[4.5]dec-8-en-8-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (50 mg, 22%), as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.55-1.73 (m, 6H), 1.75-1.87 (m, 2H), 2.93 (s, 2H), 3.05 (s, 3H), 4.66 (s, 2H), 7.12 (t, J=8.8 Hz, 2H), 7.34 (dd, J1=8.8 Hz, J2=5.2 Hz, 2H), 7.48 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 7.52-7.58 (m, 2H), 10.16 (s, 1H), 13.68 (s, br, 1H). LC-MS (ESI) calculated for C24H25FN4O6S2: 548.6, found 549.3 [M+H+].

Workup

extractionextracted with ethyl acetate (3×40 mL)
washThe combined organic layers were washed with brine (20 mL)
dry with materialdried over magnesium sulfate
filtrationfiltered
concentrationconcentrated in vacuo
dissolutionThe residue was dissolved in ethanol (5 mL)
stirringThe reaction was stirred
temperatureheated at 60° C. for 1.5 h
temperatureto cool to 25° C.
customquenched with a 0.5 M aqueous hydrochloric acid solution (10 mL)
extractionThe resulting mixture was extracted with ethyl acetate (3×40 mL)
washthe combined organic layers were washed with brine (20 mL)
dry with materialdried over magnesium sulfate
filtrationfiltered
concentrationconcentrated in vacuo
customThe crude residue was purified by prep-HPLC [Column Luna 5μ C18(2) 100 Å AXIA 150×21.2 mm, 5 micron, 30-100% in7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water]

Sources & evidence

ORD record: ord-ad96636d114d480697870ff55cb5f202
Source dataset: uspto-grants-2010_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07834009B2

Reaction notes

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