Zolpidem tartrate Chemical Properties

Melting point:

196 °C

storage temp. 

2-8°C

solubility 

Slightly soluble in water, sparingly soluble in methanol, practically insoluble in methylene chloride.

form 

Solid

color 

White to Off-White

BCS Class

1

CAS DataBase Reference

99294-93-6(CAS DataBase Reference)

Safety Information

Hazard Codes 

Xi,T,F

Risk Statements 

36/37/38-39/23/24/25-23/24/25-11

Safety Statements 

26-36-45-36/37-16-7

HS Code 

2933996500

Hazardous Substances Data

99294-93-6(Hazardous Substances Data)

Zolpidem tartrate Usage And Synthesis

Chemical Properties

White or almost white, hygroscopic, crystalline powder.

Originator

Ambien,Sanofi-Synthelabo,France

Uses

Sedativehypnotic.

Definition

ChEBI: The hemitartrate salt of zolpidem.

Manufacturing Process

18.6 g (84.8 mmol) of 3-(4-methylbenzoyl)propyldimethylamide are dissolved in 50 ml of glacial acetic acid. A solution of 13.55 g (84.8 mmol) of bromine and 45 ml of glacial acetic acid is added dropwise within 50 min at ambient temperature and the mixture is then stirred overnight. The suspension formed is filtered and washed with 30 ml of glacial acetic acid. The filter residue is added to 200 ml of distilled water, triturated thoroughly and stirred for 1 hour. The product is filtered again and washed with another 200 ml of water. The crystals obtained (21.16 g) are dried for 6 hours in a vacuum at 70°C. Yield of 3-(4-methylbenzoyl)-2-bromopropyldimethylamide is 18.18 g of white crystals (71.9% of theory), melting point: 119-121°C.
Synthesis of N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3- acetamide
1). 50 g (167.7 mmol) of 3-(4-methylbenzoyl)-2-bromopropyldimethylamide are placed in 500 ml of acetonitrile. A solution of 36.27 g (335.4 mmol) of 6- amino-3-picoline and 350 ml of acetonitrile is added dropwise at 60°C within 1.75 hours and once the solution has all been added the mixture is stirred for another 4 hours. The resulting solution is diluted with 1000 ml of dichloromethane and washed three times with 2000 ml of distilled water. Then the organic phase is extracted three times with 1000 ml of 2 N hydrochloric acid. The combined acid phases are adjusted to pH 8 with 20% sodium hydroxide solution and, after being cooled, extracted three times with 1 L of dichloromethane. The organic phases are combined, dried with magnesium sulphate and concentrated by evaporation. The crystals of N,N,6-trimethyl-2- (4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide obtained are triturated with 500 ml of distilled water, stirred overnight, filtered off, washed again with 50 ml of distilled water and the residue is dried in a vacuum for 5 hours at 60°C. Yield: 17.94 g of light-brown crystals (45.7% of theoretical).
2).10.0 g (33.5 mmol) of 3-(4-methylbenzoyl)-2-bromopropyldimethylamide and 7.25 g (67.0 mmol) of 6-amino-3-picoline are dissolved in 170 ml of 1,3- dimethyl-2-imidazolidinone and stirred for 3 hours at 60°C. The reaction mixture is cooled and diluted with 100 ml of dichloromethane. It is then washed five times with 150 ml of distilled water. The organic phase is washed twice with 150 ml of 2 N hydrochloric acid. The combined acid phases are adjusted to pH 8 with 2 N sodium hydroxide solution. The mixture is extracted twice with 150 ml of dichloromethane, the organic phases are dried with MgSO 4 and concentrated by evaporation. The brown oil obtained is mixed with 50 ml of n-heptane and stirred for 30 min. The supernatant diluent is decanted off from the precipitated product which is then washed twice with 10 ml of n-heptane. The residue is evaporated down again, combined with 200 ml of distilled water and stirred for 30 min. The N,N,6-trimethyl-2-(4- methylphenyl)imidazo[1,2-a]pyridine-3-acetamide is filtered off, washed with 50 ml of distilled water and dried. Yield: 2.38 g of beige crystals (23.1% of theoretical.), melting point: 194-195°C.
3). 100 g (0.456 mol) of 3-(4-methylbenzoyl)propyldimethylamide are dissolved in 400 ml of dichloromethane. 2 g (0.025 mol) of hydrogen bromide are piped into the solution which is then refluxed. Then 86.1 g (0.539 mol) of bromine is added dropwise within 45 min and the mixture is stirred for 30 min. It is then cooled to ambient temperature and washed with 600 ml of distilled water. The aqueous phase is discarded. The organic phase is evaporated down to about 10% (v/v) and then diluted with 300 ml of acetonitrile. This solution is added dropwise within 45 min to a solution of 66.62 g (0.616 mol) of 6-amino-3-picoline in 150 ml of acetonitrile at 70°C and stirred for 1.5 hours. Then 400 ml of toluene are added at 20-30°C and the mixture is then extracted with 500 ml of 2 N hydrochloric acid. The toluene phase is discarded, the aqueous phase is again combined with 400 ml of toluene and adjusted to pH 4 with 20% sodium hydroxide solution. The toluene phase is discarded, the aqueous phase is combined with 400 ml of toluene and adjusted to pH 8.5 with 20% sodium hydroxide solution. The toluene phase is separated off and evaporated down to 10% (v/v). The residue is combined with MTBE and stirred for 2 hours at 5°C. The crystals of N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide are suction filtered, washed with MTBE and dried. Yield: 43 g of zolpidem (30.7%).
17.94 g (94%) (54.9 mmol) of N,N,6-trimethyl-2-(4-methylphenyl)imidazo [1,2-a]pyridine-3-acetamide are placed in 90 ml of methanol. A solution of 4.13 g (27.5 mmol) of (2R,3R)-(+)-tartaric acid and 125 ml of methanol are added, followed by 28 ml of methyl-tert-butyl-ether (MTBE) within 30 seconds. The mixture is stirred for 15 hours at ambient temperature. The light-brown suspension formed is stirred for another 1 hour at 5°C, filtered off, the residue is washed with 50 ml of MTBE, and the crystals are dried for 5 hours in a vacuum at 50°C. Yield: 18.3 g crystals of N,N,6-trimethyl-2-(4- methylphenyl)imidazo[1,2-a]pyridine-3-acetamide semitartrate (87.2% of theoretical).

brand name

Ambien (Sanofi Aventis).

Therapeutic Function

Hypnotic

Pharmacokinetics

Zolpidem exhibits a high selectivity for the α1 subunit. Its good bioavailability of 72% and rapid onset of action of approximately 1.4 hours following oral absorption can be attributed to its weak base (pKa = 6.2) and high lipophilicity (mlog P = 3.85). Its pharmacokinetic profile is characterized by rapid absorption from the gastrointestinal tract and a short elimination half-life because of rapid oxidative metabolism to inactive carboxylic acid metabolites. Zolpidem undergoes CYP3A4 (major), CYP2DG, and CYP2D6 hydroxylation of the aryl methyl groups, followed by further oxidation by aldehyde dehydrogenase to the ionic carboxylic acids, which are readily eliminated in the urine.
Zolpidem demonstrates linear (dose-proportional) kinetics in the dose range of 5 to 20 mg. Although protein binding was 90%, no drug accumulation was observed following nightly dosing with 20-mg zolpidem tartrate tablets for 2 weeks. Food can prolong the time to peak concentration from 1.4 to 2.2 hours without affecting the half-life. These results suggest that for faster sleep onset, zolpidem should not be administered with or immediately after a meal. In the elderly, the dose should be 5 mg, because the elimination half-life is increased by 50% (from ~2 to ~3 hours). No accumulation was observed in elderly subjects following nightly oral dosing of 10 mg for 1 week. In patients with hepatic insufficiency, the plasma concentration doubled with an increase in the elimination half-life from approximately 2 to approximately 10 hours (range, 4–25 hours). Therefore, dosing should be modified in patients with hepatic insufficiency. No dosage adjustment should be necessary in patients with compromised renal function. Zolpidem is not hemodialyzable, but it does cross the placenta and into breast milk. Because of its longer elimination half-life (when compared to zaleplon), it may be preferred when sleep maintenance is a primary concern.

Clinical Use

Insomnia (short-term treatment)

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: metabolism accelerated by rifampicin.
Antidepressants: increased sedative effects with sertraline.
Antipsychotics: enhanced sedative effects.
Antivirals: concentration increased by ritonavir (risk of extreme sedation and respiratory depression) - avoid concomitant use.

Metabolism

Zolpidem tartrate is metabolised via several hepatic cytochrome P450 enzymes, the main enzyme being CYP3A4 with the contribution of CYP1A2. All metabolites are pharmacologically inactive and are eliminated in the urine (56
%) and in the faeces (37
%).

Zolpidem tartrate(99294-93-6)Related Product Information

• Trimethyl borate
• Metoprolol tartrate
• L(+)-Tartaric acid
• Thioacetamide
• L-Carnitine-L-tartrate
• N,N-Dimethylacetamide
• D(-)-Tartaric acid
• 2-Cyanoacetamide
• Acetamide
• Pyridine
• 6-Methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine
• Kitasamycin tartrate
• Tylosin tartrate
• Acetaminophen
• Metaraminol bitartrate
• Zonisamide
• Zolmitriptan
• 2,2-DIBROMO-1-P-TOLYLETHANONE