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

HRID 1749024Notes

Reaction equation

HRID 1749024 reaction equation
[OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6](/[CH:30]=[CH:31]/[C:32]([O:34]C)=[O:33])[CH:7]=[C:8]([F:29])[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@H:25]([CH3:28])[CH2:26][F:27])=[CH:21][CH:20]=[CH:19][CH:18]=3.CO.Cl>C1COCC1.O.CCOC(C)=O>[F:29][C:8]1[CH:7]=[C:6](/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33])[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@H:25]([CH3:28])[CH2:26][F:27])=[CH:21][CH:20]=[CH:19][CH:18]=3

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 887MethanolHCID 14798Sodium HydroxideHCID 117719383(E)-methyl 3-(3,5-difluoro-4-((1R,3R)-2-((S)-3-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate

Product 1

HCID 86345431(E)-3-(3,5-Difluoro-4-((1R,3R)-2-((S)-3-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acidYield 94.2%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

2M Sodium hydroxide (3.0 ml, 6.00 mmol) was added to a solution of (E)-methyl 3-(3,5-difluoro-4-((1R,3R)-2-((S)-3-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (275 mg, 0.60 mmol) in THF (1.5 ml)/methanol (1.5 ml). The reaction was stirred at room temperature for 3 h. EtOAc (1.5 ml) and water (15 ml) were added, then the pH of the aqueous was adjusted to ˜7 by addition of 2N HCl. The layers were separated and the aqueous was extracted with EtOAc (15 ml). The combined organics were dried over Na2SO4 and concentrated. The crude product was purified by flash silica chromatography, elation gradient 0 to 10% methanol in DCM. Pure fractions were evaporated to dryness to afford the title product (250 mg, 94%) as a pale yellow solid. 1H NMR (400 MHz, DMSO, 30° C.)δ 0.77 (3H, d), 1.06 (3H, d), 1.93 (1H, n), 2.18 (1H, dd), 2.58 (1H, dd), 2.65 (1H, dd), 2.84 (1H, dd), 3.35 (1H, dd), 4.32 (1H, d), 4.44 (1H, d), 5.16 (1H, s), 6.67 (1H, d) 6.93-7.04 (2H m), 7.21 (1H d), 7.42 (1H, d), 7.46 (2H m), 7.54 (1H, d), 10.57 (1H, s), 12.51 (1H, s). m/z: ES+ [MH]+ 443.

Workup

  1. customThe layers were separated
  2. extractionthe aqueous was extracted with EtOAc (15 ml)
  3. dry with materialThe combined organics were dried over Na2SO4
  4. concentrationconcentrated
  5. customThe crude product was purified by flash silica chromatography, elation gradient 0 to 10% methanol in DCM
  6. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-f5c13fd2fb6f4109a78c7974b782893c
Source dataset
uspto-grants-2015_10
Patent number
US09155727B2

Reaction notes

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