(+/-)-Verapamil hydrochloride Chemical Properties

Melting point:

142 °C (dec.)(lit.)

Density 

1.0596 (rough estimate)

refractive index 

1.6290 (estimate)

Flash point:

9℃

storage temp. 

2-8°C

solubility 

H₂O: >30 mg/mL

pka

8.6(at 25℃)

form 

solid

color 

white

Water Solubility 

soluble

Merck 

14,9950

BRN 

3647093

BCS Class

2

Stability:

Stable for 2 years from date of purchase as supplied. Solutions in DMSO or distilled water may be stored at -20°C for up to 3 months.

CAS DataBase Reference

152-11-4(CAS DataBase Reference)

Safety Information

Hazard Codes 

T,F

Risk Statements 

25-23/24/25-39/23/24/25-11

Safety Statements 

45-36/37/39-36/37-16

RIDADR 

UN 2811 6.1/PG 3

WGK Germany 

3

RTECS 

YV8320000

F 

8-10

HazardClass 

6.1(b)

PackingGroup 

III

HS Code 

29269090

Toxicity

LD50 in mice, rats (mg/kg): 7.6, 16 i.v.; 68, 107 s.c.; 68, 67 i.p.; 163, 114 orally (Haas, Hrtfelder)

MSDS

• Language:English Provider:alpha-(3-((2-(3,4-Dimethoxyphenyl)ethyl)methylamino)propyl)-3,4-dimethoxy-alpha-(1-methylethyl)-benzeneacetonitrile hydrochloride
• Language:English Provider:SigmaAldrich

(+/-)-Verapamil hydrochloride Usage And Synthesis

Description

Verapamil HCl (152-11-4) is a clinically useful L-type calcium channel blocker.1 It is also used as an inhibitor of drug efflux pump proteins.2

Chemical Properties

white to off-white powder

Originator

Isoptin,Knoll ,W. Germany ,1963

Uses

±)-Verapamil hydrochloride is a calcium channel modulator, adrenoceptor antagonist, anti-arrhythmic, cardiac depressant, and coronary vasodilator. It is also a calcium channel-blocker. It acts by inhibiting the slow channel entry of calcium into the cell. It acts by plugging up the channels and limiting the entry of calcium into both smooth muscle cells of arteriolar walls and the cardiac muscle cells at higher doses.

Uses

analgesic, antipyretic

Uses

Bromhexine metabolite, sodium channel blocker, decongestent secretolytic agent for respiratory diseases

Manufacturing Process

177.2 g (1 mol) of veratryl cyanide are dissolved in 1 liter of toluene in a three-neck flask. 42.9 g (1.1 mols) of pulverized sodium amide are added. The mixture is heated to boiling under reflux for one hour while stirring and excluding moisture. A solution of the base (N-methyl-N-homoveratryl)-γ- aminochloropropane, freshly prepared from 339.2 g (1.1 mols) of the hydrochloride, in 1.2 liters of toluene is added drop by drop into this boiling mixture within two hours while stirring vigorously. Heating and stirring are continued for four more hours. After cooling, the reaction mixture is poured into 3 liters of ice water while stirring, The mixture is acidified with 20% hydrochloric acid. The acidified aqueous layer is separated, neutralized by the addition of sodium hydroxide solution, and rendered alkaline by the addition of concentrated potassium carbonate solution. The precipitated oily base is taken up in benzene. On evaporating the solvent, 402 g of the crude base are obtained in the form of a reddish-brown, viscous oil.
The crude base is dissolved in a mixture of 550 ml of isopropanol and 650 ml of ethyl acetate; Gaseous hydrogen chloride is introduced into the solution until it is of weakly acidic reaction. On allowing the mixture to stand at 0°C, 365 g of α-[(N-methyl-N-homoveratryl)-γ-amino-propyl]-3,4-dimethoxyphenyl acetonitrile hydrochloride precipitate as a slightly yellowish crystal powder of the melting point 136°C to 139°C (corr.). Yield: 81% of the theoretical yield. The pure, white hydrochloride melting at 140°C to 142°C (corr.) is obtained on recrystallizing the crude salt twice from isopropanol with the addition of decolorizing carbon. The salt is very soluble in water. The base prepared from the hydrochloride in the form of an almost colorless, very viscous oil boils at 233°C to 235°C/0.01 mm Hg; nD25= 1.5532. Dioxalate, melting point: 123°C to 125°C (corr.), on recrystallization from acetone and isopropanol.
61.9 g (0.15 mol) of α-[(N-methyl-N-homoveratryl)-γ-aminopropyl]-3,4- dimethoxyphenyl acetonitrile are dissolved in 300 ml of toluene. The solution is heated to boiling under reflux with 8.5 g (1.45 x 0.15 mols) of pulverized sodium amide for one hour while stirring. Thereafter, a solution of 31.4 g (1.7 x 0.15 mols) of isopropyl bromide in 50 ml of toluene is added drop by drop thereto within 90 minutes and the mixture is kept boiling for four more hours while stirring. The cooled reaction mixture is allowed to run into 1.5 liters of ice water and the mixture is acidified with 20% hydrochloric acid. The aqueous layer is separated and is rendered alkaline by the addition of a solution of potassium carbonate. The base is taken up in warm benzene. The solvent is evaporated and the residue is distilled in a vacuum. 62.6 g of α- isopropyl-α-[(N-methyl-N-homoveratryl)-γ-aminopropy]-3,4-dimethoxyphenyl acetonitrile are obtained in the form of a light yellow, very viscous oil. Boiling point: 232°C to 235°C/0.01 mm Hg; n D 25 = 1.5460. Yield: 91.8% of the theoretical yield. Hydrochloride: melting point: 139.5°C to 140.5°C (corr.), on recrystallization from a mixture of isopropanol and ethyl acetate.

brand name

Calan (Searle); Covera (Searle); Isoptin (FSC); Isoptin (Par); Verelan (Elan).

Therapeutic Function

Coronary vasodilator, Antiarrhythmic

General Description

Pharmaceutical secondary standards for application in quality control, provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards.
Verapamil hydrochloride is a calcium channel blocker used commonly for the management of angina, supra-ventricular tachyarrhythmia, hypertension, migraine and atrial tachyarrhythmias.

Biological Activity

L-type calcium channel blocker. Vasodilator, adrenergic antagonist.

Biochem/physiol Actions

α1-adrenoceptor antagonist; L-type calcium channel blocker. Blocks L-type Ca2+ channels in smooth and cardiac muscle, induces apoptosis of human primary and metastatic colon adenocarcinoma cells in vitro. Drug resistance reversal agent acting on Pgp, e.g. decrease renal tubule elimination of digoxin. Increases basal ATPase activity of Pgp. Substrate of Cyp3A4 and CYP2C6.

storage

Room temperature

References

1) Brgden and Benfield (1996) Verapamil: a review of its pharmacological properties and therapeutic use in coronary artery disease; Drugs, 51 792 2) Safa et al. (1987) Identification of the multidrug resistance-related membrane glycoprotein as an acceptor for calcium channel blockers; J. Biol. Chem., 262 7884

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