Acetic Acid → Methyl (E)-3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]phenyl]acrylate

HRID 1749020Notes

Reaction equation

HRID 1749020 reaction equation
[F:1][C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([F:10])[C:7]=1[CH:8]=O.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][C@H:27]([NH:29][CH2:30][C:31]([F:34])([CH3:33])[CH3:32])[CH3:28])=[CH:18]1.C(O)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([F:10])[C:7]=1[C@@H:8]1[C:18]2[NH:17][C:25]3[C:20]([C:19]=2[CH2:26][C@@H:27]([CH3:28])[N:29]1[CH2:30][C:31]([F:34])([CH3:33])[CH3:32])=[CH:21][CH:22]=[CH:23][CH:24]=3

Participants

5

Reactant 3

HCID 176Acetic AcidHCID 117719359(R)-N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amineHCID 117719453(E)-methyl 3-(3,5-difluoro-4-formylphenyl)acrylate

Product 1

HCID 117719381Methyl (E)-3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]phenyl]acrylateYield 68%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

(E)-Methyl 3-(3,5-difluoro-4-formylphenyl)acrylate (6.58 g, 29.09 mmol) was added to a suspension of (R)—N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine (6.02 g. 24.24 mmol) in toluene (51.1 ml) and acetic acid (2.78 ml, 48.48 mmol). The reaction was heated to 80° C. for 5 hours. The reaction mixture was purified by ion exchange chromatography, using an SCX-2 column. The desired product was eluted from the column using 7M NH3/methanol and pure fractions were evaporated to dryness to afford a brown solid. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford the title product (7.52 g, 68.0%) as a yellow solid. 1H NMR (400 MHz, DMSO, 100° C.) δ 1.10 (3H, d), 1.12-1.31 (6H, m), 2.28-2.72 (2H, n), 2.84-3.09 (2H, m), 3.52-3.69 (1H, m), 3.76 (3H, s), 5.30 (1H, s), 6.64 (1H, d), 6.9-7.11 (2H, m), 7.21 (1H, d), 7.32 (2H, d), 7.42 (1H, d), 7.58 (1H, d), 10.14 (1H, s). m/z: ES+ [M+H]+ 457

Workup

  1. customThe reaction mixture was purified by ion exchange chromatography
  2. washThe desired product was eluted from the column
  3. customwere evaporated to dryness
  4. customto afford a brown solid
  5. customThe crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in heptane
  6. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-5c876fec52714d3ea021708128ffaaaf
Source dataset
uspto-grants-2015_10
Patent number
US09155727B2

Reaction notes

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