Ethanol → cis-N-[3-(1-benzyl-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl)-1,1-dioxo-1,4-dihydro-1lambda6-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamide

HRID 731254Notes

Reaction equation

HRID 731254 reaction equation
[CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17](O)=[O:18])=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].C(O[C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:26])C.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[O-]CC.[Na+].C(O)C>CN(C)C=O.C(O)(=O)C>[CH2:33]([N:32]1[C@@H:28]2[C@@H:27]([CH2:31][CH2:30][CH2:29]2)[C:25]([OH:26])=[C:16]([C:11]2[NH:10][C:9]3[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][C:8]=3[S:13](=[O:14])(=[O:15])[N:12]=2)[C:17]1=[O:18])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1

Participants

9

Reactant 6

HCID 702EthanolHCID 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 57671226Ethyl 2-(benzylamino)cyclopentane-1-carboxylate

Product 1

HCID 137194575cis-N-[3-(1-benzyl-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl)-1,1-dioxo-1,4-dihydro-1lambda6-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamideYield 30.3%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
25 °C

Procedure

A solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.100 g, 0.300 mmol) and 2-benzylamino-cyclopentanecarboxylic acid ethyl ester (0.074 g, 0.300 mmol) in N,N-dimethylformamide (1.5 mL) was treated with N-methylmorpholine (63.7 mg, 0.63 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60.4 mg, 0.315 mmol) and stirred at 25° C. for 4 h. The solvent was removed in vacuo. The crude material was redissolved in ethyl acetate (75 mL) and washed twice with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The crude intermediate was redissolved in ethanol (5 mL) and treated with a 21% w/w solution of sodium ethoxide in ethanol (448 μL, 1.2 mmol) and stirred for 2 h at 60° C. The reaction was allowed to cool to 25° C., treated with glacial acetic acid (0.4 mL), the solvents were removed in vacuo, and the residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, cis-N-[3-(1-benzyl-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamide (47.0 mg, 0.091 mmol, 30.3%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.43-1.61 (3H, m), 1.93-2.15 (3H, m), 3.06 (3H, s), 3.80-3.90 (1H, m), 4.40-4.52 (1H, m), 4.96 (1H, d, J=14.8 Hz), 7.27-7.34 (5H, m), 7.50-7.60 (3H, m), 10.18 (1H, s). LC-MS (ESI) calcd for C23H24N4O6S2 516.11, found 517.2 [M+H+].

Workup

  1. customThe solvent was removed in vacuo
  2. dissolutionThe crude material was redissolved in ethyl acetate (75 mL)
  3. washwashed twice with 1.0 M aqueous hydrochloric acid solution (50 mL)
  4. dry with materialThe organic layer was then dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. dissolutionThe crude intermediate was redissolved in ethanol (5 mL)
  8. stirringstirred for 2 h at 60° C
  9. temperatureto cool to 25° C.
  10. customthe solvents were removed in vacuo
  11. customthe residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% in 7 min

Sources & evidence

ORD record
ord-c994aac02ea84d76b93be242fdc825e4
Source dataset
uspto-grants-2009_09
Patent number
US07582626B2

Reaction notes

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