Dimethyl Sulfate → 2-tert-butyl 1-methyl 6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate

HRID 1710876Notes

Reaction equation

HRID 1710876 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[CH:9]1[C:19]([OH:21])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O.[CH3:25]OS(OC)(=O)=O>C1COCC1>[OH:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:19]([O:21][CH3:25])=[O:20])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:17][CH2:16]2

Participants

5

Reactant 3

HCID 6497Dimethyl SulfateHCID 168937Lithium hydroxide, monohydrateHCID 222586022-(tert-Butoxycarbonyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid

Product 1

HCID 228884912-tert-butyl 1-methyl 6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 2-(tert-butoxycarbonyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (7.4 g, 25.3 mmol) in THF (40 mL) was added LiOH.H2O (1.06 g, 25.3 mmol). The reaction mixture was stirred at room temperature for 40 min. Me2SO4 (1.19 mL, 12.63 mmol) was added and the reaction was brought to reflux for 3 h. The reaction was cooled down to room temperature and THF was removed. The residue was diluted with CH2Cl2 (150 mL), washed with H2O (2×30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on ISCO (120 g) with 0-50% ethyl acetate in hexanes over 40 minutes to yield 2-tert-butyl 1-methyl 6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate as a pale yellowish foam (3.56 g, 46%). This racemic mixture was separated by Chiral preparative HPLC using chiralpak OD 20μ column (5×50 cm, eluting with 5% (EtOH/MeOH (50:50))/Heptane with flow rate 50 mL/min). The later eluted peak is the desired (R)-2-tert-butyl 1-methyl 6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate as a white foam (1.1 g, 31%). HPLC retention time (Method B)=3.04 min. 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (d, 9H), 2.67-2.99 (m, 2H), 3.59-3.74 (m, 1H), 3.70 (s, 3H), 3.74-3.86 (m, 1H), 5.35 (s, 0.5H), 5.51 (s, 0.5H), 5.70 (s, 0.5H), 5.76 (s, 0.5H), 6.64 (s, 1H), 6.67-6.76 (m, 1H), 7.31 (d, J=8.6 Hz, 1H).

Workup

  1. temperatureto reflux for 3 h
  2. temperatureThe reaction was cooled down to room temperature
  3. customTHF was removed
  4. additionThe residue was diluted with CH2Cl2 (150 mL)
  5. washwashed with H2O (2×30 mL), brine (30 mL)
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was purified by column chromatography on ISCO (120 g) with 0-50% ethyl acetate in hexanes over 40 minutes

Sources & evidence

ORD record
ord-0e0f7bf3dc514d0b96abfbc34112e7e9
Source dataset
uspto-grants-2010_09
Patent number
US07790745B2

Reaction notes

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