Hydrochloric Acid → (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-3-hydroxy-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid

HRID 1749041Notes

Reaction equation

HRID 1749041 reaction equation
[OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6](/[CH:31]=[CH:32]/[C:33]([O:35]C)=[O:34])[CH:7]=[C:8]([F:30])[C:9]=1[C@@H:10]1[C:15]2[NH:16][C:17]3[C:22]([C:14]=2[CH2:13][C@@H:12]([CH3:23])[N:11]1[CH2:24][C:25]([F:29])([CH3:28])[CH2:26][OH:27])=[CH:21][CH:20]=[CH:19][CH:18]=3.CO.Cl>C1COCC1.CCOC(C)=O.O>[F:30][C:8]1[CH:7]=[C:6](/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34])[CH:5]=[C:4]([F:3])[C:9]=1[C@@H:10]1[C:15]2[NH:16][C:17]3[C:22]([C:14]=2[CH2:13][C@@H:12]([CH3:23])[N:11]1[CH2:24][C:25]([F:29])([CH3:28])[CH2:26][OH:27])=[CH:21][CH:20]=[CH:19][CH:18]=3

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 887MethanolHCID 14798Sodium HydroxideHCID 117719397(E)-methyl 3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-3-hydroxy-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate

Product 1

HCID 117719424(E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-3-hydroxy-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

2M Sodium hydroxide (1.27 mL, 2.54 mmol) was added to a solution of (E)-methyl 3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-3-hydroxy-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate—Isomer 1 (120 mg. 0.25 mmol) in THF (0.635 mL)/methanol (0.635 mL). The reaction was stirred at room temperature for 1 h, then diluted with EtOAc and water. The aqueous was adjusted to pH 6 by addition of 2M HCl, and the layers were separated. The aqueous layer was extracted with EtOAc, then the combined organics were dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-3-hydroxy-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid—Isomer 1 (85 mg, 72.9%) as a beige solid. 1H NMR (400 MHz, DMSO, 27° C.) 0.97 (3H, d), 1.05 (3H, d), 2.32-2.4 (1H, m), 2.44-2.54 (1H, m), 2.73-2.93 (3H, n), 3-3.14 (2H, m), 3.32-3.49 (2H, m), 4.73 (1H, s), 5.14 (1H, s), 6.58 (1H, d) 6.82-6.96 (2H, m), 7.10 (1H, d), 7.33 (1H, d), 7.36 (1H, d), 7.45 (1H, d), 10.49 (1H, s). m/z (ES+), [M+H]+=459.

Workup

  1. customthe layers were separated
  2. extractionThe aqueous layer was extracted with EtOAc
  3. dry with materialthe combined organics were dried (MgSO4)
  4. concentrationconcentrated in vacuo
  5. customThe crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM
  6. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-7be8c9be948a4e20862f3515a5a13150
Source dataset
uspto-grants-2015_10
Patent number
US09155727B2

Reaction notes

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