Sodium ethoxide → N-[3-[(4aS,8aR)-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 731327Notes

Reaction equation

HRID 731327 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+]>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

4

Reactant 2

HCID 2723922Sodium ethoxideHCID 57671179(1S,2R)-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 135955692N-[3-[(4aS,8aR)-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 40%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent2×

Conditions

Temperature
60 °C

Procedure

The crude (1S,2R)-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 (4.97 mmol) was dissolved in ethanol (50 mL) at 25° C. and a 21% w/w solution of sodium ethoxide in ethanol (2.86 mL) was added. The reaction mixture was heated to 60° C. for 8 h, then was cooled to 25° C. and partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate, decanted, and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep Flash Column 150 g; 0-6% methanol in dichloromethane) to afford the desired product, (4aS,8aR)-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 (0.96 g, 1.75 mmol, 40% over 4 steps), as a pale yellow foam. 1H NMR (400 MHz, DMSO-d6) δ: 1.10-1.26 (3H, m), 1.36-1.48 (3H, m), 1.61-1.64 (1H, m), 1.77-1.80 (1H, m), 2.27-2.31 (1H, m), 3.06 (3H, s), 3.59 (1H, bs), 4.32 (1H, bs), 4.45 (1H, s), 4.99 (1H, d, J=15.3 Hz), 7.07-7.11 (1H, m), 7.12-7.17 (2H, m), 7.29-7.33 (1H, m), 7.39-7.42 (1H, m), 7.51 (1H, dd, J1=2.3 Hz, J2=8.5 Hz), 7.57 (1H, s), 7.58-7.59 (1H, m), 10.17 (1H, s), 13.80 (1H, s). LC-MS (ESI) calcd for C24H25FN4O6S2 548.12, found 549.4 [M+H+]. >99.5% e.e. as determined by chiral HPLC analysis: column: Chiralpak AS-RH 4.6×250 mm ID 5 um, solvent: acetonitrile+0.05% trifluoroacetic acid (mobile phase B); water+0.05% trifluoroacetic acid (mobile phase A), gradient: 50% to 90% mobile phase B over 15 min.

Workup

  1. temperaturewas cooled to 25° C.
  2. custompartitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL)
  3. dry with materialThe combined organic layers were dried over sodium sulfate
  4. customdecanted
  5. concentrationwere concentrated in vacuo
  6. customThe residue was purified by flash column chromatography (Teledyne Isco RediSep Flash Column 150 g; 0-6% methanol in dichloromethane)

Sources & evidence

ORD record
ord-1b1d959079714b0f80f72328498d3352
Source dataset
uspto-grants-2009_09
Patent number
US07582626B2

Reaction notes

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