Potassium Hydroxide → 1-Bromo-5-hydroxy-5-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid

HRID 2402400Notes

Reaction equation

HRID 2402400 reaction equation
[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7]([OH:35])([C:12]3[S:13][C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([NH:24][C:25]5[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=5)[N:18]=4)=[CH:15][N:16]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:36]([O:38]C)=[O:37].[OH-].[K+]>C1COCC1.CO>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7]([OH:35])([C:12]3[S:13][C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([NH:24][C:25]5[CH:30]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:28]=[CH:27][N:26]=5)[N:18]=4)=[CH:15][N:16]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:36]([OH:38])=[O:37]

Participants

5

Reactant 2

HCID 14797Potassium HydroxideHCID 70977464Methyl 1-bromo-5-hydroxy-5-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate

Product 1

HCID 709806311-Bromo-5-hydroxy-5-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acidYield 52%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of methyl 1-bromo-5-hydroxy-5-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (50 mg, 0.081 mmol) in THF (1.6 mL) was added aqueous potassium hydroxide (172 μl, 1.61 mmol), and the mixture was stirred for 16 h at rt, after which time the reaction mixture was diluted with MeOH (2 mL), filtered, and purified by reverse phase HPLC using a C18 column and a mixture of MeCN and water modified with 0.1% TFA. The product-containing fractions were partitioned between pH 4 buffer (20 mL) and EtOAc (20 mL) and the layers were separated. The aqueous phase was extracted with EtOAc (1×20 mL)), then the combined organic phases were washed with brine (20 mL), dried, and concentrated to yield 1-bromo-5-hydroxy-5-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (25 mg, 52%) as a white solid. MS ESI calcd for C26H20BrF3N4O3S [M+H]+ 605, found 605. 1H NMR (600 MHz, dmso) δ 10.17 (s, 1H), 8.62 (s, 1H), 8.46 (d, J=5.0, 1H), 8.20 (s, 1H), 7.35-7.29 (m, 3H), 7.19 (s, 1H), 7.08 (s, 1H), 6.68 (s, 1H), 2.79 (s, 3H), 2.32-2.2.24 (m, 4H), 2.06 (br s, 1H), 1.96 (br s, 2H) ppm.

Workup

  1. filtrationfiltered
  2. custompurified by reverse phase HPLC
  3. additiona mixture of MeCN and water
  4. customThe product-containing fractions were partitioned between pH 4 buffer (20 mL) and EtOAc (20 mL)
  5. customthe layers were separated
  6. extractionThe aqueous phase was extracted with EtOAc (1×20 mL)), then the combined organic phases
  7. washwere washed with brine (20 mL)
  8. customdried
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-01d076c823434bcfa07b621c9adb2645
Source dataset
uspto-grants-2014_08
Patent number
US08796310B2

Reaction notes

Loading…