Combination for the treatment of ADHD
A composition and agonist technology, applied in the direction of drug combination, active ingredients of heterocyclic compounds, medical preparations containing active ingredients, etc., can solve problems such as cognitive impairment
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[0436] Preparation of 1-azabicyclo-2.2.1 amine:
[0437] Exo-3-amino-1-azabicyclo[2.2.1]heptane in the form of bis(p-toluenesulfonate)
[0438] (external formula-[2.2.1]-amine) synthesis:
[0439]
[0440] Step A. Preparation of 2-(benzoyloxy)-1-nitroethane (intermediate 1)
[0441] Benzoyl chloride (14.9 mL, 128 mmol) was added to a stirred solution of nitroethanol (9.2 mL, 128 mmol) in dry benzene (120 mL). The solution was refluxed for 24 hours, then concentrated in vacuo. The crude product was purified by silica gel flash chromatography. Elution with hexane-EtOAc (80:20) afforded Intermediate 1 as a white solid (68% yield): 1 H NMR (CDCl 3 )δ8.0, 7.6, 7.4, 4.9, 4.8.
[0442] Step B.E - Preparation of ethyl 4-(benzylamino)-2-butenoate (intermediate 2)
[0443] Add E-4-bromo-2-butenoic acid ethyl ester (10 mL, 56 mmol, technical grade) to stirred benzylamine (16 mL, 146 mmol) in CH 2 Cl 2 (200mL) in solution. The reaction mixture was stirred for...
Embodiment 1
[0806] Embodiment 1 (H): N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-bromo-1H-pyrazole-1-carboxamide hydrochloride:
[0807]
[0808] A solution of 4-bromopyrazole (0.52 g, 3.5 mmol) in 30 mL of EtOAc was added to excess phosgene in EtOAc (10 mL, 20% solution in toluene). After complete addition, the solution was refluxed for 1 hour, cooled and concentrated in vacuo. EtOAc was added and the mixture was concentrated again. The residue was treated with 20 mL of THF, (R)-(+)-3-aminoquinucidine dihydrochloride (0.71 g, 3.5 mmol) and excess TEA (5.0 mL, 68.1 mmol). After 60 hours, 1N NaOH was added. The mixture was washed with CHCl 3 Extracted, dried (MgSO 4 ), filtered and concentrated. The residue was subjected to flash chromatography (Biotage 40S, 90:9:1 CHCl 3 / MeOH / NH 4 OH) purification. Example 1(H) was prepared, which was recrystallized from MeOH / EtOAc to afford 289 mg (25%) of a white solid. C 11 h 15 BrN 4 HRMS (FAB) calcd for O+H: 299.0508, found: 299.0516.
Embodiment 2
[0809] Embodiment 2 (H): N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-iodo-1H-pyrazole-1-carboxamide hydrochloride:
[0810]
[0811] Phenyl chloroformate (0.75 mL, 6.0 mmol) was added dropwise to 4-iodopyrazole (1.05 g, 5.4 mmol) and TEA (0.9 mL, 6.5 mmol) in 15 mL CH 2 Cl 2 in the solution. The reaction was stirred at room temperature. After 60 hours, water was added. The mixture was washed with CH 2 Cl 2 Extracted, dried (MgSO 4 ), filtered and concentrated. Hexane was added and the solvent was removed in vacuo. A white solid formed on standing, yielding 1.6 g (95%) of phenyl 4-iodo-1H-pyrazole-1-carboxylate. MS (EI) m / z 315.1 (M + ).
[0812] Suspend 4-iodo-1H-pyrazole-1-carboxylic acid phenyl ester (1.6 g, 5.2 mmol) and (R)-(+)-3-aminoquinuclidine dihydrochloride (1.0 g, 5.2 mmol) in 10 mL of DMF. DIEA (2.7 mL, 15.5 mmol) was added dropwise. After 36 h, the solvent was removed and the residue was washed with 1N NaOH and CHCl 3 absorb. with CHCl 3 The aqueou...
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