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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 1172382
Notes
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Reaction equation

HRID 1172382 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
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 24758Sodium hydrideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 248585392H-1,2,4-Benzothiadiazine-3-acetic acid, 7-[(methylsulfonyl)amino]-, 1,1-dioxideHCID 576065982-[(4-Fluoro-benzylamino)-methyl]-5-methyl-hex-4-enoic acid ethyl ester

Product 1

HCID 135949494
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
Yield 46.4%

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 6228DimethylformamideSolvent

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

  1. extractionextracted with ethyl acetate (3×50 mL)
  2. dry with materialThe combined organic layers were dried over magnesium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. dissolutionThe residue was dissolved in ethanol (6 mL)
  6. temperatureThe reaction was heated at 70° C. for 1 h
  7. temperatureto cool to 25° C.
  8. customquenched with a 1.0 M aqueous hydrochloric acid solution (50 mL)
  9. extractionThe resulting mixture was extracted with ethyl acetate (3×50 mL)
  10. dry with materialthe combined organic layers were dried over magnesium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. 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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