Hydrochloric Acid → HCID 90338475, compound

HRID 1508776Notes

Reaction equation

HRID 1508776 reaction equation
Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12.[NH2:18][C:19]1[CH:33]=[CH:32][C:22]([CH2:23][C:24]([CH3:31])([C:28]([NH2:30])=[O:29])[C:25]([NH2:27])=[O:26])=[CH:21][CH:20]=1.Cl.O1CCOCC1>CN1C(=O)CCC1.O.C(=O)(O)[O-].[Na+].ClCCl.CO>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]3[CH2:15][CH2:16][CH2:17][C:3]3=[C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:23][C:24]([CH3:31])([C:25]([NH2:27])=[O:26])[C:28]([NH2:30])=[O:29])=[CH:32][CH:33]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 901106754-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridineHCID 90112036HCID 90112036, compound

Product 1

HCID 90338475HCID 90338475, compoundYield 72%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 13387N-methyl-2-pyrrolidoneSolventHCID 516892Sodium BicarbonateSolventHCID 21226129Dichloromethane methanolSolvent

Conditions

Temperature
150 °C

Procedure

A 10-mL microwave vial was charged with 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.100 g, 0.38 mmol), 2-(4-aminobenzyl)-2-methylmalonamide (0.167 g, 0.75 mmol) and 4M HCl in dioxane (0.095 mL, 0.38 mmol) in NMP (4 mL). The resulting mixture was heated at 150° C. under microwave irradiation for 8 h. After this time, the reaction mixture was cooled, diluted with water (20 mL) and saturated aqueous sodium bicarbonate (20 mL) affording a solid. The solid was isolated by filtration and chromatography on silica using dichloromethane/methanol (10:0 to 9:1) as eluent to afford 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)benzyl)-2-methylmalonamide (0.12 g, 72%) as an off-white solid. MW=448.94. 1H NMR (DMSO-d6, 300 MHz) δ 8.10 (s, 1H), 7.92-7.89 (m, 1H), 7.74 (dt, J=6.6, 2.1 Hz, 1H), 7.48-7.39 (m, 2H), 7.23 (s, 2H), 7.20-7.10 (m, 7H), 3.05 (s, 2H), 2.91 (t, J=7.8 Hz, 2H), 2.81 (t, J=7.2 Hz, 2H), 2.08 (quin, J=7.2 Hz, 2H), 1.14 (s, 3H). Treatment with 1.25M HCl in methanol (0.44 mL, 0.55 mmol) afforded the title compound (0.11 g, 84%) as an off-white solid. MW=485.41. M.p. 162-165° C. 1H NMR (DMSO-d6, 500 MHz) δ 14.01 (br s, 1H), 9.17 (s, 1H), 7.89 (t, J=2.0 Hz, 1H), 7.00 (dt, J=4.5, 1.5 Hz, 1H), 7.60-7.52 (m, 2H), 7.28-7.20 (m, 6H), 7.15 (s, 2H), 7.05 (s, 1H), 3.10 (s, 2H), 3.06 (t, J=7.5 Hz, 2H), 2.87 (d, J=7.5 Hz, 2H), 2.18 (quin, J=7.5 Hz, 2H), 1.15 (s, 3H); APCI MS m/z 449 [M+H]+.

Workup

  1. temperatureAfter this time, the reaction mixture was cooled
  2. customaffording a solid
  3. customThe solid was isolated by filtration and chromatography on silica

Sources & evidence

ORD record
ord-9a622a044ef04febac2e76521ec5ac6b
Source dataset
uspto-grants-2015_12
Patent number
US09221843B2

Reaction notes

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