Diisopropylethylamine → HCID 117719369, compound

HRID 1749035Notes

Reaction equation

HRID 1749035 reaction equation
FC(F)(F)S(O[CH2:7][C:8]([F:11])([CH3:10])[CH3:9])(=O)=O.FC[C@@H](C)C[N:18]1[C:30]([CH3:32])([CH3:31])[CH2:29][C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[CH:19]1[C:33]1[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42])=[CH:35][CH:34]=1.[CH:45](N(CC)C(C)C)(C)C>O1CCOCC1>[F:11][C:8]([CH3:10])([CH3:9])[CH2:7][N:18]1[C:30]([CH3:32])([CH3:31])[CH2:29][C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[CH:19]1[C:33]1[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([O:43][CH3:45])=[O:42])=[CH:35][CH:34]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 121655342-Fluoro-2-methylpropyl trifluoromethanesulfonateHCID 86342654HCID 86342654, compound

Product 1

HCID 117719369HCID 117719369, compoundYield 59.4%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

2-Fluoro-2-methylpropyl trifluoromethanesulfonate (obtained as described in Example 1, preparation of starting materials) (389 mg, 1.73 mmol) was added to a solution of (E)-methyl 3-(4-(3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (racemate) (obtained as described in Example 7, preparation of starting materials) (250 mg, 0.69 mmol) and N,N-diisopropylethylamine (0.453 ml, 2.60 mmol) in 1,4-dioxane (1.25 ml). The mixture was stirred at 95° for 64 hours and then partitioned between DCM (30 ml) and water (30 ml). The aqueous layer was extracted with DCM (20 ml) and the extracts combined with the organic layer. The combined extracts were filtered through a phase-separating paper and evaporated. The residue was purified by flash silica chromatography, elution solvent 153% EtOAc in heptane. Pure fractions were evaporated to dryness to afford (E)-methyl 3-(4-(2-(2-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (racemate) (178 mg, 59.1%) as a beige solid. The racemic product was purified by preparative HPLC (Chiralpak AD column, 20 μm silica, 50 mm diameter, 250 mm length), Heptane:Ethanol: 80:20. Fractions containing the desired compounds were evaporated to dryness to afford (E)-methyl 3-(4-(2-(2-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 1, first eluted, 70 mg) and (E)-methyl 3-(4-(2-(2-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 2, second eluted, 66 mg). 1H NMR (400 MHz, CDCl3, 30° C.) δ 1.00 (3H, s), 1.13 (3H, d), 1.20 (3H, s), 1.44 (3H, d), 2.57-2.78 (3H, m), 2.93 (1H, dd), 3.80 (3H, s), 5.05 (1H, s), 6.41 (1H, d), 7.13 (1H, ddd), 7.18 (1H, ddd), 7.32 (1H, d), 7.43 (2H, d), 7.51 (2H, d), 7.54 (1H, d), 7.64 (1, s), 7.67 (1H d). m/z: ES+ [M+H]+ 435.

Workup

  1. custompartitioned between DCM (30 ml) and water (30 ml)
  2. extractionThe aqueous layer was extracted with DCM (20 ml)
  3. filtrationThe combined extracts were filtered through a phase-separating paper
  4. customevaporated
  5. customThe residue was purified by flash silica chromatography, elution solvent 153% EtOAc in heptane
  6. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-a603e3d992bb41a4bf7ba84653dcac9e
Source dataset
uspto-grants-2015_10
Patent number
US09155727B2

Reaction notes

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