4-Methylmorpholine → rac-N-{3-[(1R,2S,7R,8S,9S,11R)-3-[(4-Fluorophenyl)methyl]-6-hydroxy-4-oxo-3-azatetracyclo[6.3.2.02,7.09,11]tridec-5-en-5-yl]-1,1-dioxo-4H-1lambda6,2,4-benzothiadiazin-7-yl}-methanesulfonamide

HRID 1751276Notes

Reaction equation

HRID 1751276 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C@H:10]2[C@@H:16]3[CH2:17][CH2:18][C@@H:12]([C@@H:13]4[C@H:15]3[CH2:14]4)[C@H:11]2[C:19](OC)=[O:20])=[CH:4][CH:3]=1.[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].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:3]=[CH:4][C:5]([CH2:8][N:9]2[C:39](=[O:40])[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:37])(=[O:36])[N:34]=3)=[C:19]([OH:20])[C@H:11]3[C@@H:10]2[C@@H:16]2[CH2:17][CH2:18][C@H:12]3[C@@H:13]3[C@H:15]2[CH2:14]3)=[CH:6][CH:7]=1

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 123590005rac-Methyl (1R,2R,4S,5S,6R,7S)-7-{[(4-fluorophenyl)methyl]amino}tricyclo[3.2.2.02,4]nonane-6-carboxylate

Product 1

HCID 137227867rac-N-{3-[(1R,2S,7R,8S,9S,11R)-3-[(4-Fluorophenyl)methyl]-6-hydroxy-4-oxo-3-azatetracyclo[6.3.2.02,7.09,11]tridec-5-en-5-yl]-1,1-dioxo-4H-1lambda6,2,4-benzothiadiazin-7-yl}-methanesulfonamideYield 80%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

The crude rac-Methyl (1R,2R,4S,5S,6R,7S)-7-{[(4-fluorophenyl)methyl]amino}tricyclo[3.2.2.02,4]nonane-6-carboxylate was dissolved in anhydrous N,N-dimethylformamide (8 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, 0.22 g, 0.66 mmol) was added followed by N-methylmorpholine (0.15 mL, 1.39 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.13 g, 0.69 mmol) was added and the mixture was stirred at 25° C. for 4 h. Triethylamine (0.28 mL, 1.98 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 1.0M 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; 0 to 20% ethyl acetate in dichloromethane) afforded the desired product, rac-N-{3-[(1R,2S,7R,8S,9S,11R)-3-[(4-Fluorophenyl)methyl]-6-hydroxy-4-oxo-3-azatetracyclo[6.3.2.02,7.09,11]trideca-5-en-5-yl]-1,1-dioxo-4H-1λ6,2,4-benzothiadiazin-7-yl}methanesulfonamide (0.50 g, 0.86 mmol, 80% over three steps), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 0.33-1.34 (10H, m), 2.30 (1H, bs), 3.06 (3H, s), 3.81 (1H, d, J=11.2 Hz), 4.48 (1H, d, J=15.6 Hz), 4.98 (1H, d, J=14.8 Hz), 7.13-7.60 (7H, m), 10.19 (1H, s). LC-MS (ESI) calcd for C27H27FN4O6S2 586.65, found 587.3 [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 1.0M 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; 0 to 20% ethyl acetate in dichloromethane)

Sources & evidence

ORD record
ord-be2ed967653f4c079235c8151bfa364b
Source dataset
uspto-grants-2015_10
Patent number
US09156832B2

Reaction notes

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