RSS-Feed abonnieren
Bitte kopieren Sie die angezeigte URL und fügen sie dann in Ihren RSS-Reader ein.
https://www.thieme-connect.de/rss/thieme/de/10.1055-s-00000084.xml
PDF herunterladen
Synthesis 2016; 48(18): 3120-3126
DOI: 10.1055/s-0035-1561865
DOI: 10.1055/s-0035-1561865
paper
A New and Practical Synthesis of Cariprazine through the Facile Construction of 2-[trans-4-(3,3-Dimethylureido)cyclohexyl]acetic Acid
Autoren
Weitere Informationen
Publikationsverlauf
Received: 20. März 2016
Accepted after revision: 25. April 2016
Publikationsdatum:
23. Juni 2016 (online)
Abstract
A new, practical, and improved synthetic route to cariprazine is described. The key step is the facile preparation of 2-[4-(3,3-dimethylureido)cyclohexyl]acetic acid in the trans configuration through direct recrystallization. The entire synthetic procedure was accomplished under mild conditions while avoiding tedious purification processes. The trans configuration of cariprazine was confirmed by X-ray crystallographic analysis.
Key words
cariprazine - antipsychotic agents - synthetic methods - recrystallization - trans configuration - X-ray crystallographySupporting Information
- Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0035-1561865.
- Supporting Information (PDF) (opens in new window)
-
References
- 1 Agai-Csongor E, Domany G, Nogradi K, Galambos J, Vago I, Keseru GM, Greiner I, Laszlovszky I, Gere A, Schmidt E, Kiss B, Vastag M, Tihanyi K, Saghy K, Laszy J, Gyertyan I, Zajer-Balazs M, Gemesi L, Kapas M, Szombathelyi Z. Bioorg. Med. Chem. Lett. 2012; 22: 3437
- 2 Citrome L. Expert Opin. Drug Metab. Toxicol. 2013; 9: 193
- 3 Meszaros GP, Agai-Csongor E, Kapas M. J. Pharm. Biomed. Anal. 2008; 48: 388
- 4 Seneca N, Finnema SJ, Laszlovszky I, Kiss B, Horvath A, Pasztor G, Kapas M, Gyertyan I, Farkas S, Innis RB, Halldin C, Gulyas B. Psychopharmacology (Berlin) 2011; 218: 579
- 5 Veselinovic T, Paulzen M, Grunder G. Expert Rev. Neurother. 2013; 13: 1141
- 6 Kiss B, Horvath A, Nemethy Z, Schmidt E, Laszlovszky I, Bugovics G, Fazekas K, Hornok K, Orosz S, Gyertyan I, Agai-Csongor E, Domany G, Tihanyi K, Adham N, Szombathelyi Z. J. Pharmacol. Exp. Ther. 2010; 333: 328
- 7 Gyertyan I, Kiss B, Saghy K, Laszy J, Szabo G, Szabados T, Gemesi LI, Pasztor G, Zajer-Balazs M, Kapas M, Csongor EA, Domany G, Tihanyi K, Szombathelyi Z. Neurochem. Int. 2011; 59: 925
- 8 Green MF, Harvey PD. Schizophr. Res. Cogn. 2014; 1: e1
- 9a Csongor EA, Galambos J, Nogradi K, Vago I, Gyertyan I, Kiss B, Laszlovszky I, Laszy J, Saghy K. US 20060229297, 2006 ; Chem. Abstr. 2006, 145, 419180.
- 9b Mathe TB, Hegedus L, Czibula L, Juhasz B, Nagy BJ, Markos DA. WO 2010070368, 2010 ; Chem. Abstr. 2010, 153, 115829.
- 9c Czibula L, Agai-Csongor E, Nogradi K, Juhasz B, Sebok F, Galambos J, Vago I. WO 2010070369, 2010 ; Chem. Abstr. 2010, 153, 116269.
- 9d Czibula L, Juhasz B, Agai-Csongor E, Sebok F, Galambos J, Nogradi K. WO 2011073705, 2011 ; Chem. Abstr. 2011, 155, 93893.
- 9e Taddei M, Cini E, Rasparini M. WO 2015056164, 2015 ; Chem. Abstr. 2015, 162, 564107.
- 10a Shonberg J, Herenbrink CK, Lopez L, Christopoulos A, Scammells PJ, Capuano B, Lane JR. J. Med. Chem. 2013; 56: 9199
- 10b Hendrick CE, Wang Q. J. Org. Chem. 2015; 80: 1059
- 11 Johnston TP, McCalet GS, Clayton SD, Frye JL, Krauth CA, Montgomery JA. J. Med. Chem. 1977; 20: 279
- 12 The byproduct was isolated by column chromatography (silica gel; CH2Cl2–MeOH, 50:1) and its structure was confirmed by 1H NMR and MS analysis. 1H NMR (400 MHz, CDCl3): δ = 7.20–7.15 (m, 2 H), 7.02–6.98 (m, 1 H), 4.50–4.48 (m, 1 H), 4.11 (q, J = 6.4 Hz, 2 H), 3.16 (br s, 4 H), 3.45 (br s, 1 H), 2.74–2.54 (m, 6 H), 2.04–2.02 (m, 2 H), 1.86–1.80 (m, 2 H), 1.53 (br s, 2 H), 1.31–1.24 (m, 4 H), 1.18–1.04 (m, 4 H). MS (ESI): m/z = 428.0 [M + H]+.
- 13 CCDC 1414994 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.