Acetic Acid → (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

HRID 1749044Notes

Reaction equation

HRID 1749044 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:35])([CH3:34])[CH2:32][OH:33])[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:35])([CH3:34])[CH2:32][OH:33])=[CH:21][CH:22]=[CH:23][CH:24]=3

Participants

5

Reactant 3

HCID 176Acetic AcidHCID 1177193443-((R)-1-(1H-indol-3-yl)propan-2-ylamino)-2-fluoro-2-methylpropan-1-olHCID 117719453(E)-methyl 3-(3,5-difluoro-4-formylphenyl)acrylate

Product 1

HCID 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)acrylateYield 10.3%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
90 °C

Procedure

(E)-methyl 3-(3,5-difluoro-4-formylphenyl)acrylate (565 mg, 2.50 mmol) was added to a suspension of 3-(((R)-1-(1H-indol-3-yl)propan-2-yl)amino)-2-fluoro-2-methylpropan-1-ol (661 mg, 2.50 mmol) in toluene (11.3 ml)/acetic acid (1.25 ml). The reaction was heated to 90° C. for 5 h. After cooling, the volatiles were removed under vacuum, then the residue was passed through an SCX-2 column, eluting with methanol to remove unreacted aldehyde. The column was then eluted with NH3/MeOH to liberate the products. The basic filtrate was evaporated then the crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford (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 1-122 mg, 10.3%) as a yellow solid and (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 2-129 mg, 11% as a yellow/orange solid. Isomer 1-1H NMR (400 MHz, CDCl3, 27° C.) 1.10 (3H, d), 1.14 (3H, d), 2.54 (1H, dd), 2.62-2.73 (1H, m), 3.06-3.3 (2H, m), 3.40 (1H, dd), 3.56 (1H, t), 3.80 (3H, s), 3.87-4.08 (1H, m), 4.27 (1H, s), 5.16 (1H, s), 6.37 (1H, d), 7.01 (2H, d), 7.07-7.15 (2H, m), 7.14-7.24 (1H, m), 7.42-7.56 (2H min), 7.71 (1H, s). m/z (ES+), [M+H]+=473. Isomer 2—1H NMR (400 MHz, CDCl3, 27° C.) 1.15 (3H, d), 1.20 (3H, d), 2.65 (1H, dd), 2.79 (1H, t), 2.93-3.09 (2H, m) 3.57 (1H, dt), 3.70 (1H, dd), 3.78 (3H, s), 4.2-4.67 (1H, n), 5.42 (1H, s), 6.32 (1H, d), 6.94 (2H, d), 7.06-7.15 (2H, m), 7.19-7.27 (2H, n, 7.42 (1H, s), 7.51 (11H, dd), 8.02 (1H, s). m/z (ES+), [M+H]+=473.

Workup

  1. temperatureAfter cooling
  2. customthe volatiles were removed under vacuum
  3. washeluting with methanol
  4. customto remove unreacted aldehyde
  5. washThe column was then eluted with NH3/MeOH
  6. customThe basic filtrate was evaporated
  7. customthe crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane
  8. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-f957ffa6716742b481eddbb3f4f1bbc2
Source dataset
uspto-grants-2015_10
Patent number
US09155727B2

Reaction notes

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