151319-34-5

Basic information

• Product Name: Zaleplon
• Synonyms: ZALEPLON;N-[3-(3-CYANO-PYRAZOLO[1,5-A]PYRIMIDIN-7-YL)-PHENYL]-N-ETHYL-ACETAMIDE;AKOS 92107;CL-284846;Sonata;N-[3-(3-cyanopyrazolo[1,5-a]py;Zaleplon and intermediates;CL-284846, N-[3-(3-Cyanopyrazolo-[1,5-a]pyrimidin-7-yl)phenyl)-N-ethylacetamide
• CAS NO: 151319-34-5
• Molecular Formula: C₁₇H₁₅N₅O
• Molecular Weight: 305.33
• EINECS: 200-659-6
• Product Categories: Active Pharmaceutical Ingredients;Zaleplon;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 151319-34-5.mol

Chemical Properties

• Melting Point: 186-1870C
• Flash Point: 9℃
• Appearance: white/
• Density: 1.25 g/cm³
• Refractive Index: 1.655
• Storage Temp.: 2-8°C
• Solubility: DMSO: ~20mg/mL
• PKA: -1.47±0.50(Predicted)
• CAS DataBase Reference: Zaleplon(CAS DataBase Reference)
• NIST Chemistry Reference: Zaleplon(151319-34-5)
• EPA Substance Registry System: Zaleplon(151319-34-5)

Safety Data

• Hazard Codes: Xi,T,F
• Statements: 36/37/38-39/23/24/25-23/24/25-11
• Safety Statements: 26-36-45-36/37-16-7
• RIDADR: UN1230 - class 3 - PG 2 - Methanol, solution
• WGK Germany: 1
• Hazardous Substances Data: 151319-34-5(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Zaleplon is used as a sedative for the treatment of insomnia, particularly in patients who have difficulty falling asleep. It acts as a selective non-benzodiazepine GABAA receptor agonist, providing a sedative effect without causing significant benzodiazepine-like side effects.
Used in Research and Forensic Applications:
Zaleplon is used as an analytical reference material for research purposes, allowing scientists to study its properties and effects on the GABAA receptor complex. It is also used in forensic applications to analyze and identify the presence of the compound in various samples.
Used in Clinical Pharmacokinetic Analysis:
Zaleplon is used in clinical pharmacokinetic studies to evaluate its rapid absorption, elimination, and metabolic pathways. These studies help to understand the compound's behavior in the human body and its potential effects on sleep latency and quality.
Used in Sleep Quality Improvement:
Zaleplon is used to improve the quality of sleep in patients with chronic insomnia. It significantly reduces sleep latency and enhances sleep quality compared to placebo without altering the normal sleep architecture.
Used in Minimizing Next-Day Residual Effects:
Due to its short half-life, Zaleplon is used to minimize next-day residual effects such as hangover, offering an advantage over benzodiazepines in terms of unwanted amnesic effects and psychomotor impairment.
Used in Avoiding Rebound Insomnia:
Zaleplon is used to prevent the occurrence of rebound insomnia at higher dosages, providing a safer alternative to benzodiazepines for the treatment of insomnia.

Manufacturing Process

N-[3-[3-(Dimethylamino)-1-oxo-2-propenyl]phenyl]acetamide amide A 1 gram-equivalent portion of N-(3-acetylphenyl)ethanamide in equivalent portion of dimethylformamide dimethyl acetal was refluxed for 8 hours, then evaporated. The residue was taken up in 200 ml of dichloromethane, passed through hydrous magnesium silicate, diluted with hexane and concentrated, giving the desired compound. N-[3-[3-(Dimethylamino)-1-oxo-2-propenyl]phenyl-N-ethylacetamide A mixture of 1 gram-equivalent of N-[3-[3-(dimethylamino)-oxo-2- propenyl]phenyl]propanamide and equivalent portion of 60% sodium hydride in oil in dimethylformamide was stirred for 0.5 hour under argon, then cooled in an ice bath and a solution of 1gram-equivalent of ethyl iodide in 10 ml of dimethylformamide was added in small portions. The mixture was then stirred at room temperature for 0.5 hour and extracted three times with hexane. The extracts were discarded, water was added and this mixture extracted with dichloromethane. This extract was evaporated and the residue crystallized from hexane giving the desired compound, MP 110°-113°C. N-[3-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide A mixture of 1 gram-equivalent of 3-aminopyrazole-4-carbonitrile and 1 gram- equivalent of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N- ethylacetanamide in 50 ml of glacial acetic acid was refluxed for 8 hours and then the solvent was removed. The residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was separated, dried, passed through a pad of hydrous magnesium silicate and hexane was added to the refluxing filtrate. The mixture was then cooled and the solid collected, giving the desired product, MP 186°-187°C.

Therapeutic Function

Sedative

Biological Activity

Non-benzodiazepine agent that acts as an agonist at the benzodiazepine site. Displays hypnotic, anxiolytic, myorelaxant and anticonvulsant activity.

Pharmacokinetics

Zaleplon displays a unique binding profile with GABAA that is distinct from the benzodiazepines but similar to that of zolpidem. Because of it greater potency for GABAA, the starting dose for zaleplon is comparable to that of zolpidem. It is rapidly absorbed, with a log P of 1.23, although only 30% of the dose is bioavailable because of rapid first-pass metabolism via liver cytosolic aldehyde oxidase/xanthine oxidase (molybdenum hydroxylases) to its major ring oxidation product, 5-oxo-zaleplon metabolite. The minor metabolism pathways include N-dealkylation from microsomal oxidation via CYP3A4 to N-desethyl-zaleplon and N-desethyl-5-oxo-zaleplon. It is rapidly metabolized by the liver, with an elimination half-life of approximately 1 hour. The oxidative metabolites are inactive, conjugated with glucuronic acid, and eliminated in the urine. Inhibitors of CYP3A4 and aldehyde oxidase can increase the plasma concentration of zaleplon significantly, although this usually does not require dosage modification. Zaleplon does not accumulate with once-daily administration and displays linear pharmacokinetics in the therapeutic range.

Metabolism

The elimination half-life of zaleplon is increased in patients with hepatic insufficiency, requiring an adjustment in dosage. High-fat meals increase the time to peak concentration and decrease the plasma concentration without affecting the half-life. These results suggest that for faster sleep onset, zaleplon should not be administered either with or immediately after a meal, which increases the time to reach peak plasma concentrations. In short-term studies (2–5 weeks), zaleplon has been shown to improve sleep quality with minimal adverse effects and no significant rebound insomnia on stopping the drug. Because of its short elimination half-life, zaleplon is quite good at getting people to sleep but is not as good at keeping people asleep. Unlike with zolpidem and eszopiclone, it has been proposed that if the patient awakens in the middle of the night (with ≥4 hours of sleep time remaining), another dose of zaleplon can be taken.

InChI:InChI=1/C17H15N5O/c1-3-21(12(2)23)15-6-4-5-13(9-15)16-7-8-19-17-14(10-18)11-20-22(16)17/h4-9,11H,3H2,1-2H3

Upstream product

• 96605-66-2 N-{3-[3-(dimethylamino)prop-2-enoyl]phenyl}-N-ethylacetamide 
• 16617-46-2 3-Amino-4-cyanopyrazole 
• 1227694-96-3 N-[3-[3-(dimethylamine)-1-oxo-2-propenyl]phenyl]-N-ethyl-acetamide 
• 16617-46-2 3-amino-4-cyano-2H-pyrazole 
• 1227694-96-3 N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide 
• 74-96-4 ethyl bromide 
• 115931-01-6 N-[3-(3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl)phenyl]acetamide 
• 99-61-6 3-nitro-benzaldehyde 
• 18293-53-3 2-trimethylsilylacetonitrile 
• 7463-31-2 3-Acetamidoacetophenone 
• 121-89-1 3-Nitroacetophenone 
• 98-86-2 acetophenone 
• 478081-97-9 3-amino-4-cyanopyrazole-hydrochloride 

Downstream Products

• 159225-99-7 5-oxo-Zaleplon 
• 1002345-34-7 7-(3-(N-ethylacetamido)phenyl)pyrazolo[1,5-a]pyrimidin-3-carboxylic acid 
• 1007130-26-8 N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide phosphate 
• 1007130-22-4 N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide hydrobromide 
• 899446-93-6 N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide hydrochloride 
• 115931-01-6 N-[3-(3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl)phenyl]acetamide 

Relevant articles and documents

Preparation method of zaleplon

The invention discloses a preparation method of zaleplon, and belongs to the technical field of medicinal chemistry. According to the method, m-nitrobenzaldehyde and triethylamine which are simple and cheap are adopted as raw materials, and a core skeleton of zaleplon is efficiently and highly selectively constructed through a one-pot cascade reaction without transition metal catalysis, so that the generation of isomers is avoided, the generation of byproducts is reduced, the yield of a target product is increased, and the synthesis cost is reduced; and simple nitro reduction modification is performed to prepare zaleplon. The whole route is short, reaction conditions are mild, operation is easy and convenient, and the method is suitable for industrial production.

Vinylation of α-Aminoazoles with Triethylamine: A General Strategy to Construct Azolo[1,5-a]pyrimidines with a Nonsubstituted Ethylidene Fragment

A new general synthesis of pharmaceutically important azolo[1,5-a]pyrimidines starting from widely available 3(5)-aminoazoles, aldehydes, and triethylamine is developed. The key is to enable the vinylation reaction that allows the in situ generation of elusive acyclic enamines and the subsequent annulation reaction to occur. This direct and practical strategy is capable of constructing a range of 5,6-unsubstituted pyrazolo[1,5-a]pyrimidines and [1,2,4]triazolo[1,5-a]pyrimidines. More importantly, this protocol provides a concise synthetic route to prepare the clinically used zaleplon.

A new method for synthesizing zaleplon (by machine translation)

The present invention provides a new method for synthesizing zaleplon. In particular, the method of the invention takes the acetophenone as raw materials, make N-ethyl-N-[ 3 - (3- dimethyl amine -1-oxo-2-propenyl) phenyl] acetamide, with 3-amino-4-cyano pyrazole reaction, forming N-[ 3 - (3-cyano-pyrazolo [1,5-α] pyrimidin-7-yl) phenyl]-N-ethyl acetamide. The synthetic route of the present invention of fewer steps, after treatment is simple, low cost, suitable for industrial production. (by machine translation)

Synthetic studies connected with the preparation of N-[3-(3- cyanopyrazolo[1,5-a]pyrimidin-5-yl)phenyl]-N-ethylacetamide, a zaleplon regioisomer

N-[3-(3-Cyanopyrazolo[1,5-a]pyrimidin-5-yl)phenyl]-N-ethyl-acetamide, a principal impurity of zaleplon, is prepared by Suzuki-Miyaura cross coupling reaction of the corresponding boronic acid and/or boronates with 5-chloropyrazolo[1,5-a]pyrimidin-3-carbonitrile (7). Various methods of preparation of both components are described, as well as approaches based on the final modification of the 5-(3-aminophenyl)-pyrazolo[1,5-a]pyrimidine-3- carbonitrile moiety prepared by Suzuki-Miyaura cross coupling. All the prepared compounds were unambiguouesly identified by NMR techniques. Spectral characteristics (IR, UV, MS) of these compounds are also given.

AN IMPROVED PROCESS FOR THE PREPARATION OF ZALEPLO

The present invention relates to an improved process for the preparation of N-[3-(3-cyanopyrazolo[ 1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide (Zaleplon) of formula (I), more particularly the present invention relates to a method for the purification of

PROCESS FOR PREPARATION OF N-[3-(3-CYANOPYRAZOLO [1,5-A]PYRIMIDIN-7-YL)PHENYL]-N-ETHYLACETAMIDE

An improved process for preparing N-[3-(3-Cyanopyrazolo [1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide, (zaleplon), comprising the steps of reacting N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide with 3-amino-4-cyanopyrazole in a reacti

N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-5-yl)phenyl]-N-ethylacetamide and crystalline forms of zaleplon

Zaleplon crystalline Forms II, III, IV and V are useful for the treatment of insomnia. These crystalline Forms are described along with processes for making them by crystallization from selected solvents. A regioisomer of zaleplon is useful as a reference

ZALEPLON SYNTHESIS

A process for making zaleplon comprises i. alkylating 3-[3-(dimethylamino)-l-oxo-2-propenyl]-phenyl]-acetamide with ethyl iodide in the presence of an alkali metal hydroxide or alkoxide in an aprotic solvent to give N-ethyl-[3-[3-(dimethylamino)-1-oxo-2-p

TWO-PHASE METHOD FOR THE SYNTHESIS OF SELECTED PYRAZOLOPYRIMIDINES

An improved method of making a substituted pyrazolopyrimidine. The method comprises reacting a aminopyrazole compound or a salt thereof with a substituted 1-oxo-2-propenyl-arene(-heterocycle) or a salt thereof under acidic conditions in a reaction medium including a two-phase mixture of an aqueous solution and a water-immiscible organic liquid. Specific substituted pyrazolopyrimidines include N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide and N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazolo[1, 5-a]-pyrimidin-7-yl}phenyl)acetamide.