Sodium ethoxide → N-{3-[(4aR,7aS)-1-(4-fluorobenzyl)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-cyclopenta[b]pyridin-3-yl]-1,1-dioxido-2H-1,2,4-benzothiadiazin-7-yl}methanesulfonamide

HRID 731266Notes

Reaction equation

HRID 731266 reaction equation
C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[N:10]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[C:11](=[O:30])[CH2:12][C:13]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][C:16]=2[S:15](=[O:29])(=[O:28])[N:14]=1)=O.[O-]CC.[Na+]>C(O)C>[F:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][N:10]2[C@@H:6]3[C@@H:5]([CH2:9][CH2:8][CH2:7]3)[C:3]([OH:2])=[C:12]([C:13]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][C:16]=4[S:15](=[O:28])(=[O:29])[N:14]=3)[C:11]2=[O:30])=[CH:33][CH:34]=1

Participants

4

Reactant 2

HCID 2723922Sodium ethoxideHCID 57671228(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}-cyclopentanecarboxylic acid methyl ester

Product 1

HCID 135955914N-{3-[(4aR,7aS)-1-(4-fluorobenzyl)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-cyclopenta[b]pyridin-3-yl]-1,1-dioxido-2H-1,2,4-benzothiadiazin-7-yl}methanesulfonamideYield 71.4%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent2×

Conditions

Temperature
60 °C

Procedure

(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}-cyclopentanecarboxylic acid methyl ester (117 mg, 0.21 mmol) was dissolved in ethanol (10 mL). A 21% w/w solution of sodium ethoxide in ethanol (0.17 mL, 0.46 mmol) was added and the mixture was stirred at 60° C. for 4 h. The reaction was allowed to cool to 25° C. and quenched with 1.0 M aqueous hydrochloric acid solution (10 mL). The mixture was extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 0-5% methanol in dichloromethane) to afford the desired product, (4aR,7aS)-N-{3-[1-(4-fluoro-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 (80 mg, 0.15 mmol, 71%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.46-1.61 (4H, m), 1.95-2.12 (2H, m), 3.07 (3H, s), 3.85 (1H, bs), 4.48 (1H, bs), 4.91 (1H, d, J=14.8 Hz), 7.16 (2H, t, J=8.4 Hz), 7.40 (2H, bs), 7.50-7.61 (3H, m), 10.18 (1H, s). LC-MS (ESI) calcd for C23H23FN4O6S2 534.58, found 535.1 [M+H+]. e.e. =98% [HPLC-analysis: Chiralpak AS-RH 4.6×250 mm, 5 micron at 25° C., 0.7 mL/min, 310 nm, t1=14.89 min, t2=22.20 min (major)]. αD=−40.76 (c=0.92, dichloromethane/methanol 1:1). Anal. calcd for C23H23FN4O6S2 0.3H2O 0.3 EtOAc 0.2 Et2O: C, 51.66; H, 4.86; N, 9.64, found C, 51.64; H, 4.90; N, 9.56.

Workup

  1. temperatureto cool to 25° C.
  2. customquenched with 1.0 M aqueous hydrochloric acid solution (10 mL)
  3. extractionThe mixture was extracted with ethyl acetate (3×20 mL)
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe crude material was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 0-5% methanol in dichloromethane)

Sources & evidence

ORD record
ord-003aa80ce2a043f9b97f8f405b3674a1
Source dataset
uspto-grants-2009_09
Patent number
US07582626B2

Reaction notes

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