Hydrochloric Acid → 3-{1'-[(1-cyclopropyl-4-methoxy-1H-indol-6-yl)carbonyl]-4-oxospiro[chroman-2,4'-piperidin]-6-yl}benzoic acid

HRID 420122Notes

Reaction equation

HRID 420122 reaction equation
C(N(CC)CC)C.[CH:8]1([N:11]2[C:19]3[C:14](=[C:15]([O:23][CH3:24])[CH:16]=[C:17]([C:20]([OH:22])=O)[CH:18]=3)[CH:13]=[CH:12]2)[CH2:10][CH2:9]1.Cl.[O:26]=[C:27]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([C:42]3[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=3)[C:45]([OH:47])=[O:46])[CH:40]=2)[O:35][C:29]2([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28]1.Cl>CN(C=O)C.O>[CH:8]1([N:11]2[C:19]3[C:14](=[C:15]([O:23][CH3:24])[CH:16]=[C:17]([C:20]([N:32]4[CH2:33][CH2:34][C:29]5([CH2:28][C:27](=[O:26])[C:41]6[C:36](=[CH:37][CH:38]=[C:39]([C:42]7[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=7)[C:45]([OH:47])=[O:46])[CH:40]=6)[O:35]5)[CH2:30][CH2:31]4)=[O:22])[CH:18]=3)[CH:13]=[CH:12]2)[CH2:9][CH2:10]1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 666494031-cyclopropyl-4-methoxy-1H-indole-6-carboxylic acidHCID 666495243-(4-Oxo-spiro[chroman-2,4'-piperidin]-6-yl)benzoic acid hydrochloride

Product 1

HCID 249632573-{1'-[(1-cyclopropyl-4-methoxy-1H-indol-6-yl)carbonyl]-4-oxospiro[chroman-2,4'-piperidin]-6-yl}benzoic acid

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

N,N′-carbonyldiimidazole (130 mg) and triethylamine (0.446 mL) were added to a solution of 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylic acid (185 mg) in DMF (4 mL), and stirred at 70° C. for 7 hours. To the reaction mixture was added 3-(4-oxo-spiro[chroman-2,4′-piperidin]-6-yl)benzoic acid hydrochloride (374 mg), which was further stirred at that temperature for 16 hours. 1 N hydrochloric acid and water were added to the reaction mixture, and the formed solid was collected by filtration. The resulting solid was recrystallized from methanol, and purified through silica gel column chromatography (chloroform/methanol) to obtain 3-{1′-[(1-cyclopropyl-4-methoxy-1H-indol-6-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}benzoic acid. This was suspended in water (5 mL), and aqueous 1 N sodium hydroxide solution (0.762 mL) was added thereto and stirred at room temperature for 30 minutes. The solution was purified through ODS reversed-phase column chromatography (water/methanol) to obtain the intended compound. 1H-NMR (400 MHz, DMSO-d6) δ: 8.11-8.09 (1H, m), 7.96-7.93 (1H, m), 7.90 (1H, dd, J=8.5, 2.4 Hz), 7.83-7.79 (1H, m), 7.56-7.50 (1H, m), 7.32 (1H, dd, J=7.6, 7.6 Hz), 7.29 (1H, d, J=3.2 Hz), 7.23 (1H, s), 7.20 (1H, d, J=8.5 Hz), 6.59 (1H, s), 6.41-6.39 (1H, m), 4.45-4.11 (1H, br m), 3.86 (3H, s), 3.86-3.55 (1H, br m), 3.52-3.22 (3H, m), 2.93 (2H, s), 2.17-1.64 (4H, br m), 1.11-1.00 (2H, m), 0.96-0.88 (2H, m); MS [M+Na]+=573.

Workup

  1. stirringwas further stirred at that temperature for 16 hours
  2. filtrationthe formed solid was collected by filtration
  3. customThe resulting solid was recrystallized from methanol
  4. custompurified through silica gel column chromatography (chloroform/methanol)

Sources & evidence

ORD record
ord-5cb339a950b842fabd0cf1e9d3970188
Source dataset
uspto-grants-2012_01
Patent number
US08093389B2

Reaction notes

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