Acetic Acid → (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

HRID 1749026Notes

Reaction equation

HRID 1749026 reaction equation
C(O)(=O)C.[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][C@H:15]([NH:17][CH2:18][C@H:19]([CH3:22])[CH2:20][F:21])[CH3:16])=[CH:6]1.[F:23][C:24]1[CH:25]=[C:26](/[CH:33]=[CH:34]/[C:35]([O:37][CH3:38])=[O:36])[CH:27]=[C:28]([F:32])[C:29]=1[CH:30]=O>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:25]=[C:26](/[CH:33]=[CH:34]/[C:35]([O:37][CH3:38])=[O:36])[CH:27]=[C:28]([F:32])[C:29]=1[C@@H:30]1[C:6]2[NH:5][C:13]3[C:8]([C:7]=2[CH2:14][C@@H:15]([CH3:16])[N:17]1[CH2:18][C@H:19]([CH3:22])[CH2:20][F:21])=[CH:9][CH:10]=[CH:11][CH:12]=3

Participants

5

Reactant 3

HCID 176Acetic AcidHCID 117719378(S)-N-((R)-1-(1H-indol-3-yl)propan-2-yl)-3-fluoro-2-methylpropan-1-amineHCID 117719453(E)-methyl 3-(3,5-difluoro-4-formylphenyl)acrylate

Product 1

HCID 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)acrylateYield 61.8%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
95 °C

Procedure

Acetic acid (2.0 ml) was added to a solution of (S)—N—((R)-1-(1H-indol-3-yl)propan-2-yl)-3-fluoro-2-methylpropan-1-amine (273 mg, 1.10 mmol) and (E)-methyl 3-(3,5-difluoro-4-formylphenyl)acrylate (obtained as described in Example 1, preparation of starting materials) (226 mg, 1 mmol) in toluene (8.0 ml). The reaction was warmed to 95° C. for 2.5 h. The volatiles were removed under vacuum, then the residue was passed through an SCX-2 column. The column was then eluted with 7M NH3/methanol to liberate the product. The filtrate was concentrated and the crude product was purified by flash silica chromatography, elution gradient 0 to 10% methanol in DCM. Pure fractious were evaporated to dryness to afford (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 (282 mg, 61.8%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, 30° C.) δ 0.82 (3H, d), 1.12 (3H, d), 1.81-1.99 (1H, m), 2.24 (1H, ddd), 2.64 (1H, ddd), 2.71 (1H, dd), 2.93-3.01 (1H, ddd), 3.42 (1H, dq), 3.81 (3H, s), 4.25-4.39 (1H, m), 4.38-4.53 (1H, m), 5.20 (1H, s), 6.39 (1H, d), 6.99 (2H, m), 7.06-7.16 (2H, m), 7.21-7.25 (1H, m), 7.52 (3H, m). m/z: ES+ [M+H]+ 457.

Workup

  1. customThe volatiles were removed under vacuum
  2. washThe column was then eluted with 7M NH3/methanol
  3. concentrationThe filtrate was concentrated
  4. customthe crude product was purified by flash silica chromatography, elution gradient 0 to 10% methanol in DCM
  5. customPure fractious were evaporated to dryness

Sources & evidence

ORD record
ord-71fec8f460dc4121bb925bce836dc667
Source dataset
uspto-grants-2015_10
Patent number
US09155727B2

Reaction notes

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