Diphenhydramine Chemical Properties

Melting point:

167-172°C

Boiling point:

bp2.0 150-165°

Density 

0.9889 (rough estimate)

refractive index 

1.5450 to 1.5490

storage temp. 

Keep in dark place,Inert atmosphere,Room temperature

solubility 

Chloroform (Slightly), Methanol (Slightly)

form 

Oil

pka

pKa 9.1 (Uncertain)

color 

Oil

Merck 

14,3309

BCS Class

1

CAS DataBase Reference

58-73-1(CAS DataBase Reference)

NIST Chemistry Reference

Ethylamine, 2-diphenylmethoxy-n,n-dimethyl-(58-73-1)

EPA Substance Registry System

Ethanamine, 2-(diphenylmethoxy)-N,N-dimethyl- (58-73-1)

Safety Information

RTECS 

KR6825000

HS Code 

2922.19.7000

Hazardous Substances Data

58-73-1(Hazardous Substances Data)

Toxicity

LD50 oral in rat: 390mg/kg

Diphenhydramine Usage And Synthesis

Description

Diphenhydramine is one of the main representatives of antihistamine drugs that block H1 receptors. Besides antihistamine activity, diphenhydramine exhibits a local anesthetic effect, relaxes smooth muscle, and has sedative and soporific action.

Originator

Benadryl,Parke Davis,US,1946

Uses

Diphenhydramine also reduces muscle rigidity and general stiffness, and has a relatively minor effect on tremors.

Uses

Diphenhydramine is used for symptoms of allergies, for treating hives, hay fever, serum sickness, and other allergic illnesses, and also as a sedative and soporific drug as an independent as well as in combination with other drugs. Synonyms of this drug are dimedrol, benadryl, allergina, valdren, and many others.

Uses

Antihistaminic.

Definition

ChEBI: Diphenhydramine is an ether that is the benzhydryl ether of 2-(dimethylamino)ethanol. It is a H1-receptor antagonist used as a antipruritic and antitussive drug. It has a role as a H1-receptor antagonist, an antiemetic, a sedative, an anti-allergic agent, a muscarinic antagonist, an antiparkinson drug, an antipruritic drug, a local anaesthetic, an antidyskinesia agent, an antitussive and a oneirogen. It is an ether and a tertiary amino compound.

Manufacturing Process

As described in US Patent 2,421,714: (a) benzhydryl
omide is first prepared as follows: 840 parts by weight of diphenylmethane is heated to 130°C with stirring. In the presence of a 200 watt electric light 6 inches from the flask, 880 parts of
omine is added slowly. Liberation of H
occurs and addition requires 1 hour and 45 minutes. The temperature is maintained at 130°C for an additional 30 minutes. A fine stream of air is blown in to remove H
and
2 while the reaction mixture cools. Benzene (180 parts) is added and the solution used immediately in (b) below.
If pure benzhydryl
omide is desired the above reaction mixture is dissolved in ether, washed with water, sodium carbonate solution and finally with water. The ether is removed, benzene added and distilled off and the benzhydryl
omide distilled in vacuo. Yield 85%.
(b) 490 parts β-dimethylaminoethanol and 530 parts of anhydrous sodium carbonate are heated to 110°C with stirring. The addition of the benzenebenzhydryl
omide mixture is then begun. The temperature is raised to 120°- 125°C. As reaction takes place carbon dioxide is evolved, the addition requires1? hours. The mixture is kept at 125°C for 5 hours additional time. After cooling, 3,000 parts of water is added and the mixture stirred until the inorganic salts are dissolved. The mixture is transferred to a large separatory funnel and 1,500 parts of ether added. The ether solution is washed several times with water and then the ether layer extracted with 1 to 4 hydrochloric acid. The acid solution is treated with 30 parts of Darco and 30 parts Filter-Cel and filtered.
The free base is liberated from the acid solution with 20% sodium hydroxide solution and taken up in ether. The ether layer is washed with water, saturated with NaCl and then shaken with solid potassium hydroxide. The ether is removed by distillation, 200 parts of benzene added and distilled off. The residue is distilled in vacuo and the fraction 150°-165°C/2 mm is collected and amounts to 433 parts. The hydrochloride salt is prepared by dissolving the free base in anhydrous ether and slowly adding an alcoholic solution of hydrogen chloride. The solid is recrystallized from absolute alcohol-ether mixture or isopropanol-ether mixture and has a MP of 161-162°C.

Therapeutic Function

Antihistaminic

Trade name

Benadryl (Parke-Davis)

Contact allergens

This antihistaminic drug with sedative properties is mainly sold over the counter. It can be used both topically (treatment of pruritis) and orally for its antiallergic, antiemetic, sedative, and anticough properties. Allergic or photoallergic contact dermatitis and fixeddrug eruption seem to be rare.

Safety Profile

Deadly human poison by an unspecified route. Poison by ingestion, intravenous, intraperitoneal, and subcutaneous routes. Experimental reproductive effects. Human systemic effects by ingestion: somnolence, alteration of operant conditioning, changes in psychophysiological tests. Human mutation data reported. When heated to decomposition it emits toxic fumes of NO,. See also ETHERS.

Synthesis

Diphenhydramine, 2-diphenylmethoxy-N,N-dimethylamine (10.2.5), is synthesized by the esterification of 2-dimethylaminoethanol with benzhydrylbromide [35¨C37].

Environmental Fate

Diphenhydramine is fairly stable in the environment although it does undergo photodegradation. Conjugates of diphenhydramine such as diphenhydramine-N-glucuronide may be converted back to the parent compound, diphenhydramine, through enzymatic cleavage during sewage treatment process. Diphenhydramine is removed poorly through wastewater treatment processes and is found in significant concentrations in aquatic organisms downstream from such plants.
Diphenhydramine has significant risk for bioaccumulation, particularly in water downstream from wastewater and sewage treatment facilities.

Solubility in water

One gram of diphenhydramine is soluble in 1 mL of water, 2 mL of ethanol, 2 mL of chloroform, or 50 mL of acetone; the compound is very slightly soluble in benzene or ether.

Toxicity evaluation

The toxicity of antihistamines is related to their anticholinergic (antimuscarinic), antihistamine, and serotonergic activation. The action of acetylcholine at the muscarinic receptors is blocked, resulting in signs and symptoms of anticholinergic poisoning. Diphenhydramine may produce direct toxicity unrelated to its anticholinergic properties including inhibition of cardiac fast sodium channels and at higher concentrations, the drug may inhibit potassium channels, which can result in QT prolongation. Diphenhydramine also blocks the reuptake of serotonin and has been reported to cause serotonin syndrome in some individuals during overdose. The action of diphenhydramine at H-1 receptors causes sedation.

Diphenhydramine(58-73-1)Related Product Information

• Dimethyl sulfide
• Biphenyl
• 2-Methylaminoethanol
• Monoethanolamine
• 2,2-Diethoxyethylamine
• N,N-Dimethylethylamine
• Dimethyl carbonate
• m-Anisyl alcohol
• Dimethyl sulfoxide
• Dimethyl fumarate
• Dimethyl sebacate
• L-1-Phenylethylamine
• o-Anisaldehyde
• N,N-Dimethylformamide
• 4-Dimethylaminobenzaldehyde
• Dimethyl ether
• (Trifluoromethoxy)benzene
• 4-Dimethylaminopyridine