Diisopropylethylamine → (E)-methyl 3-(3,5-difluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2, 3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate

HRID 1749031Notes

Reaction equation

HRID 1749031 reaction equation
FC(F)(F)S(O[CH2:7][C@H:8]([CH3:11])[CH2:9][F:10])(=O)=O.[CH3:14][C:15]1([CH3:42])[NH:27][CH:26]([C:28]2[C:33]([F:34])=[CH:32][C:31](/[CH:35]=[CH:36]/[C:37]([O:39][CH3:40])=[O:38])=[CH:30][C:29]=2[F:41])[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:34][C:33]1[CH:32]=[C:31](/[CH:35]=[CH:36]/[C:37]([O:39][CH3:40])=[O:38])[CH:30]=[C:29]([F:41])[C:28]=1[CH:26]1[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16][C:15]([CH3:14])([CH3:42])[N:27]1[CH2:7][C@H:8]([CH3:11])[CH2:9][F:10])=[CH:24][CH:23]=[CH:22][CH:21]=3

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 117719349(E)-methyl 3-(4-(3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylateHCID 117719393(S)-3-fluoro-2-methylpropyl trifluoromethanesulfonate

Product 1

HCID 117719334(E)-methyl 3-(3,5-difluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2, 3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylateYield 56.5%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

(S)-3-Fluoro-2-methylpropyl trifluoromethanesulfonate (obtained as described in Example 3, preparation of starting materials) (0.339 g, 1.51 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)-3,5-difluorophenyl)acrylate (0.3 g, 0.76 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.458 ml, 2.65 mmol) in 1,4-dioxane (2 ml). The stirring was continued for 24 hours then the volatiles were removed under vacuum and the crude product was purified by flash silica chromatography, elution gradient 0 to 25% EtOAc in heptane. Pre fractions were evaporated to dryness to afford (E)-methyl 3-(3,5-difluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (0.202 g, 36%) as a white solid. The material was combined with another batch (0.36 g) and purified by preparative HPLC (Chiralpak IA column, 20 μm silica, 20 mm diameter, 250 mm length), Heptane:IPA 70:30 at 80 ml/min (4 injections). Fractions containing the desired compounds were evaporated to yield (E)-methyl 3-(3,5-difluoro-4-(2-((S)-3-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, 217 mg) and (E)-methyl 3-(3,5-difluoro-4-(2-((S)-3-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, 165 mg). Analysis was done on Chiralpak IA column, 5 μm silica, 4.6 mm diameter, 50 mm length, Heptane:IPA 70:30 at 2 ml/min. 1H NMR (400 MHz, DMSO, 30° C.) δ 0.50 (3H, d), 1.02 (3H, s), 1.30 (3H, s), 2.11 (1H, dd), 2.62 (2H, d), 2.80 (1H, d), 2.99 (1H, dd), 3.74 (3H, s), 4.09-4.23 (1H, m), 4.29 (1H, d), 5.09 (1H, s), 6.81 (1H, d), 6.97 (2H, dt), 7.16 (1H, d), 7.39 (1H, d), 7.53 (2H, d), 7.64 (1H, d), 10.44 (1H, s). m/z: ES+ [M+H]+ 471.

Workup

  1. customthe volatiles were removed under vacuum
  2. customthe crude product was purified by flash silica chromatography, elution gradient 0 to 25% EtOAc in heptane
  3. customPre fractions were evaporated to dryness

Sources & evidence

ORD record
ord-6dceeb78c7844d63906c38d3d6aa8433
Source dataset
uspto-grants-2015_10
Patent number
US09155727B2

Reaction notes

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