Hydrochloric Acid → Setrobuvir

HRID 2408778Notes

Reaction equation

HRID 2408778 reaction equation
C(O[C:4]([C@H:6]1[C@@H:11]([N:12]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C:13](=[O:32])[CH2:14][C:15]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][C:18]=3[S:17](=[O:31])(=[O:30])[N:16]=2)[C@H:10]2[CH2:41][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])C.[O-]CC.[Na+].Cl>C(O)C.C(OCC)(=O)C>[F:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][N:12]2[C:13](=[O:32])[C:14]([C:15]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][C:18]=4[S:17](=[O:31])(=[O:30])[N:16]=3)=[C:4]([OH:5])[C@H:6]3[C@@H:11]2[C@H:10]2[CH2:41][C@@H:7]3[CH2:8][CH2:9]2)=[CH:35][CH:36]=1

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 2723922Sodium ethoxideHCID 66674926(1S,2R,3S,4R)-3-{(4-fluorobenzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1lambda6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester

Product 1

HCID 135565932SetrobuvirYield 68.1%

Reagents, catalysts & solvents 2

HCID 702EthanolSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of (1S,2R,3S,4R)-3-{(4-fluorobenzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (209.3 mg, 0.345 mmol) in absolute ethanol (3 mL) was added a 21 wt. % solution of sodium ethoxide in ethanol (0.51 mL, 1.37 mmol). After stirring at 60° C. for 2 h, the mixture was diluted with ethyl acetate and acidified with 1.0 M aqueous hydrochloric acid solution to pH 1. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified by flash column chromatography (Teledyne ISCO RediSep column, 0 to 100% ethyl acetate in hexanes) to afford N-{3-[(1R,2S,7R,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 (131.5 mg, 0.235 mmol, 68% yield) as an off-white solid. 1H NMR (400 MHz, MeOH-d4) δ: 1.28 (2H, d, J=11.0 Hz), 1.47 (1H, t, J=10.8 Hz), 1.57-1.74 (3H, m), 2.56 (1H, d, J=3.2 Hz), 2.75 (1H, d, J=2.3 Hz), 2.96 (1H, d, J=9.2 Hz), 3.02 (3H, s), 3.58 (1H, d, J=9.2 Hz), 4.42 (1H, d, J=15.5 Hz), 5.03 (1H, d, J=15.7 Hz), 7.04 (2H, t, J=8.5 Hz), 7.31 (2H, dd, J1=7.9 Hz, J2=5.5 Hz), 7.37 (1H, d, J=8.8 Hz), 7.54 (1H, dd, J1=8.3 Hz, J2=2.3 Hz), 7.69 (1H, d, J=2.3 Hz). LC-MS (ESI) calcd for C25H25FN4O6S2 (M+H+) 561.13. found 561.4. ee=98.5% [HPLC-analysis: Chiralpak AS-RH 2.1×150 mm, 5 micron at r.t., Solvent A-Solvent B (see table above for gradient), 0.3 mL/min, 312 nm, t1=7.58 min (major), t2=8.95 min]

Workup

  1. customThe organic layer was separated
  2. extractionthe aqueous layer was extracted with ethyl acetate (2×20 mL)
  3. dry with materialThe combined organic layer was dried over anhydrous magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe crude mixture was purified by flash column chromatography (Teledyne ISCO RediSep column, 0 to 100% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-da70a2113d394536ad6f9dfeda17fb69
Source dataset
uspto-grants-2014_08
Patent number
US08815847B2

Reaction notes

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