4-Methylmorpholine → N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-3-methyl-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1lambda6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide

HRID 1617042Notes

Reaction equation

HRID 1617042 reaction equation
[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C@H:8]2[C@H:13]3[CH2:14][C@H:10]([CH2:11][CH2:12]3)[C@H:9]2[C:15](OC)=[O:16])=[CH:4][C:3]=1[CH3:21].[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].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:38](=[O:39])[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:36])(=[O:35])[N:33]=3)=[C:15]([OH:16])[C@H:9]3[C@@H:8]2[C@H:13]2[CH2:14][C@@H:10]3[CH2:11][CH2:12]2)=[CH:4][C:3]=1[CH3:21]

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 8471TriethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 248585392H-1,2,4-Benzothiadiazine-3-acetic acid, 7-[(methylsulfonyl)amino]-, 1,1-dioxideHCID 66674907methyl (1S,2R,3S,4R)-3-(4-fluoro-3-methyl-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylate

Product 1

HCID 135976571N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-3-methyl-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1lambda6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamideYield 68%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

Methyl (1S,2R,3S,4R)-3-(4-fluoro-3-methyl-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylate (0.090 g, 0.31 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 0.10 g, 0.31 mmol) was added followed by N-methylmorpholine (0.071 mL, 0.65 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.062 g, 0.32 mmol) was added and the mixture was stirred at 25° C. for 4 h. Triethylamine (0.13 mL, 0.92 mmol) was added and the mixture was stirred at 50° C. for 16 h. Upon cooling to 25° C., the solution was diluted with ethyl acetate (50 mL) and washed with 1.0 M aqueous hydrochloric acid solution (2×50 mL), saturated aqueous brine solution (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. Purification by flash column chromatography (Teledyne Isco RediSep column; 50 to 100% ethyl acetate in hexanes) afforded the desired product, N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-3-methyl-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.12 g, 0.21 mmol, 68%), as a white powder. 1H NMR (400 MHz, CDCl3) δ: 1.43-2.85 (9H, m), 2.29 (3H, s), 3.07 (3H, s), 3.45-3.47 (1H, m), 5.17-5.21 (2H, m), 6.95-7.05 (3H, m), 7.59-7.66 (3H, m). LC-MS (ESI) calcd for C26H27FN4O6S2 574.64, found 575.3 [M+H+].

Workup

  1. dissolutiondissolved, approximately 5 min
  2. stirringthe mixture was stirred at 25° C. for 4 h
  3. stirringthe mixture was stirred at 50° C. for 16 h
  4. washwashed with 1.0 M aqueous hydrochloric acid solution (2×50 mL), saturated aqueous brine solution (20 mL)
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customto afford a golden oil
  9. customPurification by flash column chromatography (Teledyne Isco RediSep column; 50 to 100% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-3cf5df87c83f472f8e213ab43038f93c
Source dataset
uspto-grants-2014_07
Patent number
US08765741B2

Reaction notes

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