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 1749015Notes

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.C(=O)([O-])[O-].[K+].[K+]>O.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

Conditions

Temperature: 80 °C

Procedure

Under an atmosphere of nitrogen, (E)-Methyl 3-(3,5-difluoro-4-formylphenyl)acrylate (0.606 kg, 2.65 mol) and (R)—N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine (33% w/w solution in toluene, 2.0 kg, 2.65 mol) were charged to a 20 L vessel followed by toluene (4.22 L). Acetic acid (304 ml, 5.31 mol) was added to the vessel. The mixture was agitated and heated to 80° C. The mixture was agitated at 80° C. overnight before being cooled to 20° C. A solution of potassium carbonate (0.916 kg, 6.63 mol) in water (3.3 L) was added to the mixture. The mixture was stirred for 10 minutes before the agitator was switched off and the layers were allowed to separate. The aqueous layer was removed and discarded. Water (3.3 L) was charged to the reactor. The mixture was agitated for 10 minutes then allowed to stand for 10 minutes. The lower aqueous phase was removed and the organic layer was allowed to stand at room temperature overnight. The batch was heated to 80° C. Heptane (4.61 L) was added to the hot solution over 35 minutes. The stirred mixture was held at approximately 80° C. for 1 hour. The mixture was cooled to 30° C. over 2 hours during which time the product crystallised. The slurry was stirred at 30° C. for 2.5 hours. The solid was isolated by filtration. The reactor vessel walls were washed with heptane and the washings were used to wash the filter cake. The solid was dried in vacuo to afford (E)-methyl 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 as a pink solid (0.763 kg, 61%). 1H NMR (400 MHz, DMSO, 27° C.) δ 1.06 (3H, d), 1.13 (3H, d), 1.21 (3H, d), 2.35 (1H, dd), 2.58 (1H, dd), 2.8-2.98 (2H, m), 3.44-3.61 (1H, m), 3.74 (3H, s), 5.24 (1H s), 6.80 (1H, d), 6.9-7.05 (2H, m), 7.19 (1H, d), 7.41 (1H, d), 7.50 (2H, d), 7.63 (1H, d), 10.58 (1H, s). m/z: ES+ [M+H]+ 457.

Workup

stirringThe mixture was agitated at 80° C. overnight
temperaturebefore being cooled to 20° C
stirringThe mixture was stirred for 10 minutes before the agitator
customto separate
customThe aqueous layer was removed
additionWater (3.3 L) was charged to the reactor
stirringThe mixture was agitated for 10 minutes
customThe lower aqueous phase was removed
waitto stand at room temperature overnight
temperatureThe batch was heated to 80° C
additionHeptane (4.61 L) was added to the hot solution over 35 minutes
waitThe stirred mixture was held at approximately 80° C. for 1 hour
temperatureThe mixture was cooled to 30° C. over 2 hours during which time the product
customcrystallised
stirringThe slurry was stirred at 30° C. for 2.5 hours
customThe solid was isolated by filtration
washThe reactor vessel walls were washed with heptane
washto wash the filter cake
customThe solid was dried in vacuo

Sources & evidence

ORD record: ord-568191398c3347b1877a295fb954d994
Source dataset: uspto-grants-2015_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09155727B2

Reaction notes

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