Uses
Dehydro Aripiprazole (Aripiprazole EP Impurity E; Aripiprazole USP Related Compound G) is an impurity of Aripiprazole (A771000), a selective dopamine D2-receptor antagonist with dopamine autoreceptor agonist activity.
General Description
Dehydro Aripiprazole is the primary, active metabolite of aripiprazole, marketed as the atypical antipsychotic Abilify
for the treatment of schizophrenia, bipolar disorder, and clinical depression. This new certified solution standard is suitable for use in LC or GC applications including forensic or clinical toxicology analysis and urine drug testing.
Synthesis
The general procedure for the synthesis of 7-[4-[4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy]-3,4-dihydroquinolin-2(1H)-ones from 7-(4-(4-(4-(2,3-dichlorophenyl)-1-piperazinyl)butoxy)-2(1H)-quinolinone was as follows:
Example 1: Large-scale synthesis of dehydroaripiprazole [7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2(1H)-one] (Compound 1; Formula VI) Aripiprazole (Formula VIA)
1. 15 g (0.03 mol) of 7-(4-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one was dissolved in 360 mL of anhydrous tetrahydrofuran to form a clarified solution.
2. 12 mL (0.16 mol) of trifluoroacetic acid was added to the solution.
3. 24.3 g (0.11 mol) of 1,2-dichloro-4,5-dicyanoquinone was added and the mixture was stirred at room temperature under a nitrogen atmosphere.
4. After the reaction was stirred for 40 minutes, TLC assay showed complete consumption of the raw material.
5. 1.5 L of water was added and then the reaction mixture was alkalized to pH 12 with 50% NaOH aqueous solution.
6. The reaction mixture was extracted with dichloromethane (3 x 300 mL), the organic phases were combined and dried with MgSO4.
7. The crude product was purified by column chromatography using silica as stationary phase and dichloromethane to 10% methanol/dichloromethane as eluent. 8. The product was purified by 2-propanolysis.
8. The product was further purified by recrystallization from 2-propanol to give 13.7 g (92%) of off-white solid target product.
Product characterization:
1H-NMR (400 MHz, CDCl3) δ 12.33 (1H, br s), 7.72 (1H, d), 7.42 (1H, d), 7.16-7.11 (2H, m), 6.98-6.93 (1H, dd), 6.83-6.79 (2H, m), 6.53 (1H, d), 4.10 (2H, t), 3.09 (4H, br), 4.10 (2H, t), 4.10 (2H, t). 3.09 (4H, br s), 2.67 (4H, br s), 2.52 (2H, t), 1.93-1.70 (4H, m).
LCMS (acidic method) [M + H]+ 446.02, rt 14.246 min.
References
[1] Patent: US2011/275803, 2011, A1. Location in patent: Page/Page column 60-61
[2] Crystal Growth and Design, 2013, vol. 13, # 5, p. 2036 - 2046
[3] Heterocyclic Communications, 2005, vol. 11, # 6, p. 485 - 490
