4-Methylmorpholine → HCID 135976585, compound

HRID 1751219Notes

Reaction equation

HRID 1751219 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][CH:3]=1.[CH3:21][S:22]([NH:25][C:26]1[CH:41]=[CH:40][C:29]2[NH:30][C:31]([CH2:36][C:37](O)=[O:38])=[N:32][S:33](=[O:35])(=[O:34])[C:28]=2[CH:27]=1)(=[O:24])=[O:23].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:37](=[O:38])[C:36]([C:31]3[NH:30][C:29]4[CH:40]=[CH:41][C:26]([NH:25][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:27][C:28]=4[S:33](=[O:35])(=[O:34])[N:32]=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:19][CH:20]=1

Participants

9

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 66674915HCID 66674915, compound

Product 1

HCID 135976585HCID 135976585, compoundYield 46.3%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

Methyl (1S,2S,3R,4R)-3-[(4-fluorobenzyl)amino]bicyclo[2.2.1]heptane-2-carboxylate (0.087 g, 0.3 mmol) was dissolved in anhydrous N,N-dimethylformamide (2.8 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, 0.1 g, 0.3 mmol) was added followed by N-methylmorpholine (0.07 mL, 0.63 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.061 g, 0.315 mmol) was added and the mixture was stirred at 25° C. for 4 h. Triethylamine (0.126 mL, 0.9 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 (25 mL) and washed with 1.0M aqueous hydrochloric acid solution (2×25 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. The oil was dissolved in methanol (4 mL) and the product was precipitated by the addition of 1.0M aqueous hydrochloric acid solution (4 mL) while stirring. The solid was collected by vacuum filtration and further dried in vacuo to afford the desired product, N-{3-[(1R,2R,7S,8S)-3-(4-fluoro-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 (0.0781 g, 0.139 mmol, 46%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.23-1.48 (6H, m), 2.67-2.68 (2H, m), 3.06 (3H, s), 3.24 (1H, d, J=15.0 Hz), 3.72 (1H, d, J=11.9 Hz), 4.07 (1H, d, J=15.6 Hz), 5.12 (1H, d, J=15.7 Hz), 7.14 (2H, t, J=8.4 Hz), 7.39 (2H, dd, J1=8.2 Hz, J2=5.8 Hz), 7.51 (1H, dd, J1=8.4 Hz, J2=2.3 Hz), 7.57-7.60 (2H, m), 10.18 (1H, s). LC-MS (ESI) calcd for C25H25FN4O6S2 560.12, found 561.3 [M+H+]. ee=99% [HPLC-analysis: Chiralpak AS-RH 4.6×250 mm, 5 micron at r.t., Solvent A-Solvent B (see table for gradient), 0.8 mL/min, 310 nm, t1=7.58 min, t2=10.08 min (major)].

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 (2×25 mL), saturated aqueous brine solution (10 mL)
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customto afford a golden oil
  9. customthe product was precipitated by the addition of 1.0M aqueous hydrochloric acid solution (4 mL)
  10. stirringwhile stirring
  11. filtrationThe solid was collected by vacuum filtration
  12. customfurther dried in vacuo

Sources & evidence

ORD record
ord-98334a1f72c5432f82e8ac86e80c9143
Source dataset
uspto-grants-2015_10
Patent number
US09156832B2

Reaction notes

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