Hydrochloric Acid → N-[3-[(4aR,8aS)-1-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-4a,5,6,7,8,8a-hexahydroquinolin-3-yl]-1,1-dioxo-4H-1$l^{6},2,4-benzothiadiazin-7-yl]methanesulfonamide

HRID 731272Notes

Reaction equation

HRID 731272 reaction equation
CO[C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[N:11]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[C:12](=[O:31])[CH2:13][C:14]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:17]=2[S:16](=[O:30])(=[O:29])[N:15]=1)=[O:4].[O-]CC.[Na+].Cl>C(O)C>[F:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][N:11]2[C@@H:6]3[C@@H:5]([CH2:10][CH2:9][CH2:8][CH2:7]3)[C:3]([OH:4])=[C:13]([C:14]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][C:17]=4[S:16](=[O:30])(=[O:29])[N:15]=3)[C:12]2=[O:31])=[CH:38][CH:37]=1

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 2723922Sodium ethoxideHCID 57671232(1R,2S)-2-{(4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1lambda6-benzo[1,2,4] thiadiazin-3-yl)-acetyl]-amino}-cyclohexanecarboxylic acid methyl ester

Product 1

HCID 135955915N-[3-[(4aR,8aS)-1-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-4a,5,6,7,8,8a-hexahydroquinolin-3-yl]-1,1-dioxo-4H-1$l^{6},2,4-benzothiadiazin-7-yl]methanesulfonamideYield 30%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent2×

Conditions

Temperature
60 °C

Procedure

The crude (1R,2S)-2-{(4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclohexanecarboxylic acid methyl ester (0.3 mmol) was dissolved in ethanol (4 mL). A 21% w/w solution of sodium ethoxide in ethanol (0.448 mL, 1.2 mmol) was added into the above solution. The mixture was stirred at 60° C. for 4 h. Upon cooling to 25° C., the mixture was poured into 1.0 M aqueous hydrochloric acid solution (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a light yellow solid. Purification by flash column chromatography (Teledyne Isco RediSep Flash Column; 5% methanol in dichloromethane) afforded the desired product, (4aR,8aS)-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2,4a,5,6,7,8,8a-octahydro-quinolin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (49.7 mg, 0.09 mmol, 30% over two steps), as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.13-2.34 (8H, m), 3.06 (3H, s), 3.46-3.69 (1H, m), 4.24-4.66 (2H, m), 4.98 (1H, d, J=16 Hz), 7.16 (2H, t, J=8 Hz), 7.39-7.59 (5H, m), 10.15 (1H, s). LC-MS (ESI) calcd for C24H25FN4O6S2 548.12, found 549.2 [M+H+].

Workup

  1. temperatureUpon cooling to 25° C.
  2. extractionThe aqueous layer was extracted with ethyl acetate (2×50 mL)
  3. dry with materialThe organic layer was dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customto afford a light yellow solid
  7. customPurification by flash column chromatography (Teledyne Isco RediSep Flash Column; 5% methanol in dichloromethane)

Sources & evidence

ORD record
ord-b74ede0625d54b4abf0918ea54207d8b
Source dataset
uspto-grants-2009_09
Patent number
US07582626B2

Reaction notes

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