Hydrochloric Acid → ((S)-4-hydroxy-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester

HRID 1645143Notes

Reaction equation

HRID 1645143 reaction equation
[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[CH:8]=[N:7]1)[CH3:2].C(N(CC)CC)C.Cl>C(N(CC)CC)C.C(O)=O>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@H:10]([OH:15])[C:9]=2[CH:8]=[N:7]1)[CH3:2]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 59152894Ethyl 2-(4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate

Product 1

HCID 59152908((S)-4-hydroxy-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl esterYield 85%

Reagents, catalysts & solvents 1

HCID 11084032Triethylammonium formateSolvent

Procedure

To a stirred solution of (4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (16.7 g, 75.0 mmol) in formic acid-triethylamine azeotropes (molar fraction of triethylamine: 0.2857, 45 mL) was added chloro-[(1S,2S)—N-(p-toluenesulfonyl)-1,2-diphenylethanediamine](mesitylene)ruthenium(II) (1.86 g, 3.0 mmol). The reaction mixture was stirred at room temperature for 3 hours and then at 45° C. for 2.5 hours with occasional venting. After cooling to room temperature, 1N hydrochloric acid (50 mL) was added, followed by extraction with ethyl acetate (200 mL×3). The separated organic layers were combined, washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (gradient elution, 0-4% methanol in dichloromethane) to afford ((S)-4-hydroxy-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (14.3 g, 85%) as a white solid with enantiomeric purity ≧99% as determined by Chiralpak™ IA column (condition: gradient: 50% hexane in ethanol, flow rate: 15 mL/min and retention time: 5.8 min for enantiomer A and 8.1 min for enantiomer B). 1H NMR (400 MHz, CD3OD) δ ppm 7.47 (s, 1 H), 4.89 (d, 4 H), 4.76 (d, 1 H), 4.20 (q, J=7.2 Hz, 2 H), 2.52 (m, 2 H), 2.06-1.84 (m, 4 H), 1.29 (t, J=7.2 Hz, 3 H). MS calcd. for C11H16N2O3 224, obsd. (ESI+) [(M+H)+] 225.

Workup

  1. waitat 45° C. for 2.5 hours with occasional venting
  2. temperatureAfter cooling to room temperature
  3. extractionfollowed by extraction with ethyl acetate (200 mL×3)
  4. washwashed with brine (300 mL)
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by column chromatography (gradient elution, 0-4% methanol in dichloromethane)

Sources & evidence

ORD record
ord-c790e145f0b344dda63fedc931c3c31e
Source dataset
uspto-grants-2012_02
Patent number
US08124641B2

Reaction notes

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