4-Methylmorpholine → HCID 178442220, compound

HRID 1172398Notes

Reaction equation

HRID 1172398 reaction equation
C(O[C:4](=[O:21])[CH2:5][CH:6]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])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.[O-]CC.[Na+]>CN(C)C=O>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:12]2[CH:6]([CH2:7][CH2:8][CH:9]([CH3:10])[CH3:11])[CH2:5][C:4]([OH:21])=[C:37]([C:32]3[NH:33][S:34](=[O:35])(=[O:36])[C:29]4[CH:28]=[C:27]([NH:26][S:23]([CH3:22])(=[O:25])=[O:24])[CH:42]=[CH:41][C:30]=4[N:31]=3)[C:38]2=[O:39])=[CH:19][CH:18]=1

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 2723922Sodium ethoxideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 248585392H-1,2,4-Benzothiadiazine-3-acetic acid, 7-[(methylsulfonyl)amino]-, 1,1-dioxideHCID 57606600HCID 57606600, compound

Product 1

HCID 178442220HCID 178442220, compoundYield 36%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

A solution of 3-(4-fluoro-benzylamino)-6-methyl-heptanoic acid ethyl ester (93 mg, 0.315 mmol), (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (105 mg, 0.315 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (73 mg, 0.378 mmol) in anhydrous N,N-dimethyformamide (4 mL) was treated with N-methyl morpholine (0.083 mL, 0.756 mmol). The reaction was stirred under a nitrogen environment at 50° C. for 18 h, quenched with a 6.0 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 sodium ethoxide (470 μL, 21% w/w, 1.26 mmol). The reaction was heated at 60° C. under a nitrogen environment for 18 h. The reaction mixture was allowed to cool to 25° C., quenched with a 1.0 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 80% ethyl acetate in hexanes) to afford the desired product, N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-6-(3-methyl-butyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,2-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (63.6 mg, 36%) as a white powder. 1H NMR (400 MHz, CDCl3) δ: 0.90 (6H, d, J=6.9 Hz), 1.08-1.27 (2H, m), 1.50-1.75 (3H, m), 2.60 (1H, d, J=17.3 Hz), 2.95-3.01 (1H, m), 3.06 (3H, s), 3.37-3.49 (1H, m), 3.98 (1H, d, J=14.9 Hz), 5.30 (1H, d, J=15.0 Hz), 7.03-7.08 (2H, m), 7.20-7.28 (3H, m), 7.46 (1H, bs), 7.65-7.67 (1H, m), 7.71-7.73 (1H, m). LC-MS calculated for C25H29FN4O6S2: 564.2, found 565.5 [M+H+].

Workup

  1. customquenched with a 6.0 M aqueous hydrochloric acid solution (50 mL)
  2. extractionextracted with ethyl acetate (2×50 mL)
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. dissolutionThe resulting oil was dissolved in ethanol (5 mL)
  7. temperatureThe reaction was heated at 60° C. under a nitrogen environment for 18 h
  8. temperatureto cool to 25° C.
  9. customquenched with a 1.0 M aqueous hydrochloric acid solution (50 mL)
  10. extractionextracted with ethyl acetate (2×50 mL)
  11. washwashed with brine (50 mL)
  12. dry with materialdried with sodium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated in vacuo
  15. customThe crude resin was purified by flash column chromatography (ISCO RediSep column, 0 to 80% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-d96edb6e291e4f64a641bc98810791bf
Source dataset
uspto-grants-2010_11
Patent number
US07834009B2

Reaction notes

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