152-11-4 Usage
Uses
Used in Pharmaceutical Industry:
(+/-)-Verapamil hydrochloride is used as a secondary standard for quality control, providing pharmaceutical laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards.
Used in Cardiovascular Applications:
(+/-)-Verapamil hydrochloride is used as a calcium channel modulator, adrenoceptor antagonist, anti-arrhythmic, cardiac depressant, and coronary vasodilator. It acts by inhibiting the slow channel entry of calcium into the cell, 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.
Used in Pain Management:
(+/-)-Verapamil hydrochloride is used as an analgesic and antipyretic, helping to relieve pain and reduce fever.
Used in Respiratory Applications:
(+/-)-Verapamil hydrochloride is used as a sodium channel blocker and decongestent secretolytic agent for respiratory diseases, aiding in the treatment and management of respiratory conditions.
Used in Management of Various Conditions:
(+/-)-Verapamil hydrochloride is commonly used for the management of angina, supra-ventricular tachyarrhythmia, hypertension, migraine, and atrial tachyarrhythmias, providing relief and treatment for these conditions.
Originator
Isoptin,Knoll ,W. Germany ,1963
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.
Therapeutic Function
Coronary vasodilator, Antiarrhythmic
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.
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
Check Digit Verification of cas no
The CAS Registry Mumber 152-11-4 includes 6 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 3 digits, 1,5 and 2 respectively; the second part has 2 digits, 1 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 152-11:
(5*1)+(4*5)+(3*2)+(2*1)+(1*1)=34
34 % 10 = 4
So 152-11-4 is a valid CAS Registry Number.
InChI:InChI=1/C27H38N2O4.ClH/c1-20(2)27(19-28,22-10-12-24(31-5)26(18-22)33-7)14-8-15-29(3)16-13-21-9-11-23(30-4)25(17-21)32-6;/h9-12,17-18,20H,8,13-16H2,1-7H3;1H
152-11-4Relevant articles and documents
PROCESS FOR THE PREPARATION OF VERAPAMIL
-
Paragraph 0067, (2021/12/31)
The present invention relates to a process for the preparation of α-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]propyl]-3,4-dimethoxy-α-(1-methylethyl), monohydrochloride (verapamil hydrochloride, a compound of formula I), the process comprising treating verapamil (a compound of formula IA) with alkyl haloformate and/or sodium dihydrogen phosphate, followed by treating with hydrochloric acid to get verapamil hydrochloride in good yield and good purity.
A PROCESS FOR THE PREPARATION OF VERAPAMIL HYDROCHLORIDE
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Page/Page column 11, (2016/12/01)
The present invention relates to a process for the preparation of 5-(3,4-dimethoxyphenylethyl) methyl-amino-2-(3,4-dimethoxyphenyl)-2-isopropyl valeronitrile, which is known as Verapamil. The present invention also relates to a process for improving the purity of verapamil and therefore of its hydrochloride represented as the compound of formula I, by efficient removal of the impurities formed, affording a product of purity greater than 99 %. The process of the present invention is simple, efficient, cost-effective and industrially feasible.
PROCESS FOR PREPARING N-METHYL-3, 4-DIMETHOXYPHENYLETHYLAMINE
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Page/Page column 6, (2009/07/17)
Provided are intermediates useful for the preparation of verapamil and methods for their preparation.
A process for the resolution of racemic verapamil
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Page/Page column 5, (2009/01/24)
A new process is described for the resolution of racemic verapamil, which allows the desired enantiomer to be obtained in high yields and with high enantiomeric purity. The process uses optically active 2,3-bis[(2-fluorobenzoyl)oxy]butanedioic acid as the
Process for the resolution of racemic verapamil
-
Page/Page column 3, (2009/01/20)
A new process is described for the resolution of racemic verapamil, which allows the desired enantiomer to be obtained in high yields and with high enantiomeric purity. The process uses optically active 2,3-bis[(2-fluorobenzoyl)oxy]butanedioic acid as the resolving agent, and a water/dimethylformamide or water/acetonitrile or water/methanol mixture, as the reaction solvent.
A scaleable route to the pure enantiomers of verapamil
Bannister, Robin M.,Brookes, Michael H.,Evans, Graham R.,Katz, Ruth B.,Tyrrell, Nicholas D.
, p. 467 - 472 (2013/08/07)
A versatile route to single enantiomer verapamil from readily available raw materials is described. The key intermediate, 4-cyano-4-(3,4-dimethoxyphenyl)-5-methyl hexanoic acid (verapamilic acid), was resolved efficiently with α-methyl benzylamine. Stereochemical integrity at the quaternary carbon centre was preserved through subsequent steps to give either (R)-or (S)-verapamil in good overall yield. This sequence incorporated a selective borane-mediated reduction of a tertiary amide. Process scale-up to the pilot plant has been demonstrated successfully for the resolution step.
Compound and process
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, (2008/06/13)
A process for the preparation of a compound of formula (VI), optionally in enantiomerically-enriched form (R or S), comprises chemoselective reduction of a novel compound of formula (V), wherein Ar1 and Ar2 are independently selected from optionally-substituted aromatic or heteroaromatic groups having upto 20 C atoms, Ak is C1-20 alkyl, and R is H or C1-20 alkyl. STR1
Preparation of phenylacetonitriles carrying basic substituents
-
, (2008/06/13)
A process for the preparation of phenylacetonitriles, carrying basic substituents, of the formula I STR1 where R1, R2, R3, R4, R5, R6, R7 and R8 have the meanings given in the description, by reacting an aldehyde of the formula II STR2 with an amine of the formula III STR3
