Lithium hydroxide, monohydrate → HCID 68295415, compound

HRID 572519Notes

Reaction equation

HRID 572519 reaction equation
[C:1]([O:5][CH:6]([C:11]1[N:12]([CH3:32])[C:13](=[O:31])[C:14]2[C:19]([C:20]=1[N:21]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[CH:24]=1)[CH3:22])=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].O.Cl.O>C1COCC1.CO>[C:1]([O:5][CH:6]([C:11]1[N:12]([CH3:32])[C:13](=[O:31])[C:14]2[C:19]([C:20]=1[N:21]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[CH:24]=1)[CH3:22])=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 3

HCID 168937Lithium hydroxide, monohydrateHCID 21885828Hydrate;hydrochlorideHCID 68294975HCID 68294975, compound

Product 1

HCID 68295415HCID 68295415, compoundYield 48.4%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a mixture of methyl 2-(4-((3,4-dimethylphenyl)(methyl)amino)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-hydroxyacetate (90 mg, 0.237 mmol) and amberlyst 15 resin (45 mg, 0.237 mmol) in DCM (3 mL) at −70° C. was bubbled a stream of isobutylene until the volume doubles. The tube was sealed, and the reaction was stirred at room temperature for 10 hours. The mixture was filtered through a short pad of silica gel, washed with DCM and EtOAc, and the filtrate was concentrated. The mixture was purified on silica using EtOAc/hexanes 0-40% to give the intermediate methyl ester as an off-white solid (41.6 mg, 39%). 1H NMR (400 MHz, CDCl3) δ ppm 8.56-8.44 (m, 1 H), 7.59-7.42 (m, 3 H), 7.26-7.14 (m, 1 H), 7.05-6.93 (m, 1 H), 6.03-5.82 (m, 2 H), 3.74-3.67 (m, 7 H), 3.33 (s, 4 H), 2.23-2.12 (m, 6 H), 1.38-1.22 (m, 4 H), 1.12-1.00 (m, 9 H); ES-LCMS: 437.4 (M+1). To a solution of methyl 2-(tert-butoxy)-2-(4-((3,4-dimethylphenyl)(methyl)amino)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (41.6 mg) in THF (3.0 mL) and MeOH (1 mL) was added a solution of LiOH/water (1.183 mL, 1.183 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was cooled to 0° C. and 1N HCl/water was added to pH˜3 and the mixture was purified by reverse phase HPLC on a C18 column using MeCN/water 10-90% containing 0.05% TFA to provide the title compound as an off-white solid (19.5 mg, 19%). 1H NMR (400 MHz, CDCl3) ppm 8.58-8.42 (m, 1 H), 7.62-7.45 (m, 2 H), 7.21-7.12 (m, 1 H), 7.02-6.58 (m, 2 H), 6.02 (s, 1 H), 3.79-3.63 (m, 3 H), 3.41 (s, 3 H), 2.30-2.07 (m, 6 H), 1.27-1.08 (m, 9 H); ES-LCMS: 423.4 (M+1).

Workup

  1. temperatureThe mixture was cooled to 0° C.
  2. customthe mixture was purified by reverse phase HPLC on a C18 column
  3. additioncontaining 0.05% TFA

Sources & evidence

ORD record
ord-30678d00365746c388ad409b0df4a812
Source dataset
uspto-grants-2015_05
Patent number
US09029391B2

Reaction notes

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