Methanol → HCID 68631898, compound

HRID 2098974Notes

Reaction equation

HRID 2098974 reaction equation
[F:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9]([CH2:12][C:13]([OH:15])=[O:14])([CH3:11])[CH2:8][CH2:7]2.S(=O)(=O)(O)O.[CH3:23]O>>[CH3:23][O:14][C:13](=[O:15])[CH2:12][C:9]1([CH3:11])[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:16][CH3:17])[C:2]=2[F:1])[CH2:7][CH2:8]1

Participants

4

Reactant 3

HCID 887MethanolHCID 1118Sulfuric AcidHCID 59590827HCID 59590827, compound

Product 1

HCID 68631898HCID 68631898, compound

Procedure

The racemic carboxylic acid 38.4 (180 mg, 0.77 mmol) was dissolved in MeOH (40 mL) and a catalytic amount of concentrated sulfuric acid was added. The solution was heated to reflux and stirred for 4 hours. The reaction was concentrated under reduced pressure and diluted with EtOAc, washed with water, and washed with a saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate to give the racemic (7-fluoro-6-methoxy-1-methyl-indan-1-yl)-acetic acid methyl ester (194 mg, 0.77 mmol). The racemic methyl ester was subsequently dissolved in dichloroethane (8.0 mL) and cooled to 0° C. To the solution was added ethanethiol (0.17 mL, 2.4 mmol) followed by aluminum chloride (310 mg, 2.3 mmol). The reaction mixture was then warmed to room temperature and stirred for one hour. The reaction was diluted with DCM (300 mL) and washed with saturated sodium bicarbonate solution (200 mL). The aqueous layer was extracted with DCM (3×300 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was then passed through a plug of silica using an EtOAc:DCM mixture to give racemic 7-fluoro-6-hydroxy-1-methyl-indan-1-yl)-acetic acid methyl ester (170 mg, 93%). The racemic material was then purified by chiral HPLC (column: AD; solvent: 5% IPA/hexane) to yield 38.5 (64 mg, 38%) (retention time 30 minutes) and 38.6 (61 mg, 36%) (retention time 55 minutes). One of either 38.5 or 38.6 has the R stereochemistry at the β carbon and the other has the S stereochemistry at the β carbon. MS ESI (pos.) m/e: 239.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 6.75-6.87 (m, 2H), 5.20 (br. s., 1H), 3.64 (s, 3H), 2.87 (t, J=7.2 Hz, 2H), 2.66-2.84 (m, 2H), 2.33 (dt, J=12.9 Hz, 7.4 Hz, 1H), 1.99 (dt, J=13.0 Hz, 7.4 Hz, 1H), 1.46 (s, 3H).

Workup

  1. temperatureThe solution was heated
  2. temperatureto reflux
  3. concentrationThe reaction was concentrated under reduced pressure
  4. additiondiluted with EtOAc
  5. washwashed with water
  6. washwashed with a saturated sodium bicarbonate solution
  7. dry with materialThe organic layer was dried over sodium sulfate

Sources & evidence

ORD record
ord-c76ac3bfc797445ba83aed4fec8909ee
Source dataset
uspto-grants-2013_05
Patent number
US08450522B2

Reaction notes

Loading…