Reinvestigation of the Synthesis of Ketanserin (5) and its Hydrochloride Salt (5.HCl) via 3‐(2‐Chloroethyl)‐2,4‐(1H,3H)‐quinazolinedione (2) or Dihydro‐5H‐oxazole(2,3‐b)quinazolin‐5‐one (1)

Abstract

The synthesis of ketanserin (5) and its hydrochloride salt (5.HCl) using respectively equimolar amounts of 3‐(2‐chloroethyl)‐2,4‐(1H,3H)‐quinazolinedione (2) with 4‐(parafluorobenzoyl)piperidine (3) and dihydro‐5H‐oxazole(2,3‐b)quinazolin‐5‐one (1) with hydrochloride salt of 4‐(parafluorobenzoyl)piperidine (3.HCl) is reinvestigated. The one‐pot reaction of ethyl‐2‐aminobenzoate with ethyl chloroformate and ethanol amine has afforded 3‐(2‐chloroethyl)‐2,4‐(1H,3H)‐quinazolinedione (2) (86%) that was then refluxed with 4‐(parafluorobenzoyl)piperidine (3) in ethyl methyl ketone in the presence of sodium carbonate to obtain free base of ketanserin (87%). In another attempt, a very pure hydrochloride salt of ketanserin (5.HCl) was synthesized using equimolar amounts of dihydro‐5H‐oxazole(2,3‐b)quinazolin‐5‐one (1) and hydrochloride salt of 4‐(parafluorobenzoyl)piperidine (3.HCl) by a solvent‐less fusion method. Thus, under optimized conditions, 180°C and a reaction time of 30 min, the powder mixture was transformed into glassy crystals that were initially readily soluble in chloroform but were transformed afterwards over time (2 h) to white precipitates (5.HCl) suspended in chloroform with a yield of 72%.

Asymmetric Synthesis of Trifluoroethyl-Based, Chiral 3-Benzyloxy-1- and -2-Phenyl-quinazolinones of Biomedicinal Interest by Radical Type Cross-Coupling to Olefins

“…The higher energy (and thus less stability) in the latter complex-16 may be attributed to the unfavorable steric interaction between the tert-butyl group and the 3OH-Quiz chelates (1)(2)(3) in view of the C-H to N-O vDW repulsion. This weakness explains why the reaction time was much longer and in a range of 50 h to 4-5 days (cf 30 h to 2-3.5 days by using 3-DMP catalyst).…”

“…Quinazolin-4-ones and -2,4-diones (Quizones) have been well documented as an important template of potential pharmacological and biochemical interests. Relevant studies of Ketanserin in these areas have strongly suggested that these derivatives can be used for treating hypertensive symptoms by reducing peripheral vascular resistance by blocking the effect of serotonin functions (Figure 1) [1,2]. In addition, an amide variant TCMDC-125133 bearing a chiral α-Quizone group was found to exhibit effective antimalarial activity against the Plasmodium falciparum 3D7 strain (Figure 1) [3,4].…”

DMAP-Catalyzed One-Pot Synthesis of Quinazoline-2,4-diones from 2-Aminobenzamides and Di-tert-butyl Dicarbonate

“…Quinazolinediones are an important class of nitrogen-containing heterocycles in medicinal chemistry with a broad range of bioactivities, such as antihypertensive, , antidiabetic, antimicrobial, , antimalarial, , and anticancer activities. − Structures shown in Figure are representative examples of commercial drugs or biologically active compounds and natural products containing the quinazoline-2,4-dione core. − Among them, Zenarestat is a therapeutic agent against diabetic neuropathy. Due to the importance of quinazoline-2,4-diones in medicinal chemistry, various synthetic methods have been reported to construct this core. − The representative strategies for the construction of quinazoline-2,4-diones have been summarized in the introduction part of our previous article .…”

Synthesis of N-Unsubstituted and N3-Substituted Quinazoline-2,4(1H,3H)-diones from o-Aminobenzamides and CO2 at Atmospheric Pressure and Room Temperature

“…Quinazoline-2,4­(1 H ,3 H )-diones are important building blocks for the production of various bioactive compounds and commercial drugs, such as linagliptin, sotrastaurin, tioperidone, nitraquazone, and ketanserin, containing at least one quinazoline moiety. The traditional approach employed to produce this important class of compounds usually utilized phosgene and related agents, which have the disadvantages of requiring toxic reagents and multistep procedures.…”

“…The results are represented in Scheme A. The antihypertensive drug pelanserin ( 2ap ) was easily synthesized in 99% yield within 2 h. Cloperidone ( 2aq ) and ketanserin ( 2ar ), also antihypertensive drugs, were produced in 96% and 94% yields in 4 h, respectively. It is important to mention that many important drugs containing quinazolinedione skeletons have differential substituents on the N 1- and N 3-positions, which generally cannot be selectively embedded.…”