Citric Acid → (6-Hydroxy-3,4-dihydro-1H-isoquinolin-2-yl)-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanone

HRID 1611413Notes

Reaction equation

HRID 1611413 reaction equation
[CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[S:5][C:6]=1[C:7]([OH:9])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Br.[OH:43][C:44]1[CH:45]=[C:46]2[C:51](=[CH:52][CH:53]=1)[CH2:50][NH:49][CH2:48][CH2:47]2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(N(CC)CC)C.C(Cl)Cl>[OH:43][C:44]1[CH:45]=[C:46]2[C:51](=[CH:52][CH:53]=1)[CH2:50][N:49]([C:7]([C:6]1[S:5][C:4]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[N:3][C:2]=1[CH3:1])=[O:9])[CH2:48][CH2:47]2

Participants

8

Reactant 5

HCID 311Citric AcidHCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27756634-Methyl-2-(4-(trifluoromethyl)phenyl)-5-thiazolecarboxylic acidHCID 133617991,2,3,4-Tetrahydroisoquinolin-6-ol--hydrogen bromide (1/1)

Product 1

HCID 22256691(6-Hydroxy-3,4-dihydro-1H-isoquinolin-2-yl)-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanoneYield 42.1%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 8471TriethylamineSolvent

Procedure

4-Methyl-2-[4-(trifluoromethyl)phenyl]-5-thiazolecarboxylic acid (450 mg, 1.6 mmol), 1-hydroxybenzotriazole (260 mg, 1.9 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (370 mg, 1.9 mmol) were added to 6-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (300 mg, 1.3 mmol) in 2 ml of triethylamine and 6 ml of methylene chloride. The reaction was stirred under N2 at RT for 18 hrs. The reaction was diluted with 100 ml CH2Cl2 and made acidic with 10% citric acid. The organic layer was separated and the aqueous phase was extracted with 2×100 ml CH2Cl2. The organic phases were combined, washed with H2O, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (40% EtOAc/Hexanes) to yield 229 mg (42%) of the title product of this preparation as a white solid.

Workup

  1. customThe organic layer was separated
  2. extractionthe aqueous phase was extracted with 2×100 ml CH2Cl2
  3. washwashed with H2O, brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified by flash column chromatography (40% EtOAc/Hexanes)
  8. customto yield

Sources & evidence

ORD record
ord-2e0c1096438c4b48b1c1bbc6662902c6
Source dataset
uspto-grants-2006_01
Patent number
US06987118B2

Reaction notes

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