111470-99-6

Basic information

• Product Name: Amlodipine Besylate
• Synonyms: Vazkor;3-Ethyl 5-Methyl 2-(2-Aminoethoxy)methyl-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate Benzenesulfonate 2-(2-Aminoethoxy)methyl-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic Acid 3-Ethyl 5-Methyl Ester Benzenesulfona;3-ethyl 5-Methyl 2-((2-aMinoethoxy)Methyl)-4-(2-chlorophenyl)-6-Methyl-1,4-dihydropyridine-3,5-dicarboxylate benzenesulfonate;AMlodipine bes;2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid-3-ethyl 5-methyl ester, benzenesulfonate (1:1);Amlodipine besylate Amlodipine besilate;2-(2-Aminoethoxy)methyl-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic Acid 3-Ethyl 5-Methyl Ester Benzenesulfonate;3-Ethyl 5-Methyl 2-(2-Aminoethoxy)methyl-4-(2-chlorophenyl)-6-methyl-1,4-dihydro
• CAS NO: 111470-99-6
• Molecular Formula: C₆H₆O₃S*C₂₀H₂₅ClN₂O₅
• Molecular Weight: 567.05094
• EINECS: 1312995-182-4
• Product Categories: BENICAR;AZD929;Fine Chemical;Active Pharmaceutical Ingredients;Dihydropyridine Class Chemicals;Intermediates & Fine Chemicals;Pharmaceuticals;Amlodipine;Aromatics;Dihydropyridine;Heterocycles
• Mol File: 111470-99-6.mol
• Article Data: 20

Chemical Properties

• Melting Point: 199-201°C
• Boiling Point: 527.2 ºC at 760 mmHg
• Flash Point: 272.6 ºC
• Appearance: white/solid
• Density: 1.227 g/cm³
• Vapor Pressure: 3.34E-11mmHg at 25°C
• Storage Temp.: Store at RT
• Solubility: DMSO: 20 mg/mL
• PKA: 8.6
• Water Solubility: Soluble in DMSO (20 mg/mL), water (10 mM), chloroform, ethanol (14 mg/mL), and methanol.
• Merck: 14,491
• CAS DataBase Reference: Amlodipine Besylate(CAS DataBase Reference)
• NIST Chemistry Reference: Amlodipine Besylate(111470-99-6)
• EPA Substance Registry System: Amlodipine Besylate(111470-99-6)

Safety Data

• Hazard Codes: Xn
• Statements: 22-36/37/38-20/21/22
• Safety Statements: 26-36
• WGK Germany: 3
• RTECS: US7967700
• Hazardous Substances Data: 111470-99-6(Hazardous Substances Data)

Usage

Mechanism of action

Amlodipine Besylate is a dihydropyridine calcium antagonist that prevents the transmembrane influx of calcium ions into the vascularsmooth and cardiacmuscle.It attaches to both dihydropyridine and non-dihydropyridine binding sites. The contractile manners of cardiac and vascular smooth muscle are dependent on the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine Besylate inhibits calcium ion influx across cell membranes selectively, with a superior effect on vascular smooth muscle cells than on cardiac muscle cells.

Clinical Use

Amlodipine besylate (ADB) is an important secondgeneration calcium channel blocker that belongs to the dihydropyridine family. It is used for the treatment of hypertension and angina. It is more selective for arterial vascular smooth muscle than for the cardiac tissue. It is approved for the treatment of hypertension and for variant and stable angina and may also be used for dilated cardiomyopathy. ADB has ameliorating effects on the plasma and myocardial catecholamine levels and significantly reduces calcium deposition. It has a negative inotropic effect on the heart that results in a decrease in heart work load. https://baqai.edu.pk/baqaiassets/bjhs//admin/articlefiles/1525325965upl0.pdf

side effects

1. Heart Failure Calcium-channel blockers are normally avoided in patients with heart failure but ADB has not been found to have any adverse effects on morbidity or mortality in patients with severe heart failure. Therefore, it may be a suitable treatment option for angina pectoris or hypertension in such patients. However, a study on hypertensive patients found that ADB was less effective than the diuretic chlorthalidone in the prevention of heart failure. 2. Porphyria Although there have been reports of the successful use of ADB in patients with porphyria, some studies have reported the occurrence of acute exacerbation in such patients. 3. Miscellaneous Adverse Effects A number of other adverse events occurring in response to the regular use of ADB in 1091 patients with hypertension have been reported. Around 12% (128) patients stopped the intake of the drug due to the appearance of adverse effects. The most common reported adverse effects include ankle edema, flushing, headache, skin rash, and fatigue.

Interaction with Combination Drugs

The evaluation of pharmacokinetic interactions between Amlodipine Besylate(ADB), valsartan and hydrochlorothiazide revealed no clinically relevant interactions. Similarly, combination of ADB and olmesartan medoxomil is also known to have no impact on the pharmacokinetic profiles of individual drugs. Concomitant use of ADB and atorvastatin in patients with hypertension and dyslipidemia has shown to be well tolerated without any adverse pharmacodynamic interaction. The use of triple combination i.e. ADB + Olmesartan Medoxomil + hydrochlorothiazide has also demonstrated to be safe .

References

[1] http://www.webmd.com/drugs/2/drug-5891/amlodipine-oral/details [2] https://www.drugs.com/amlodipine.html [3] https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b4b30c56-7403-4f69-9a8e-3d82a37e8bc5#section-1

Chemical Properties

White Crystalline Solid

Originator

Pfizer (USA)

Uses

Different sources of media describe the Uses of 111470-99-6 differently. You can refer to the following data:
1. A dihydropyridine calcium channel blocker. Used as an antianginal and antihypertensive
2. Angiotensin II inhibitor prodrug, antihypertensive
3. Amlodipine besylate is a L-type calcium channel blocker which may be used for the treatment of angina pectoris and hypertension. Amlodipine also inhibits growth of human epidermoid carcinoma A431 cells and has antireproductive effects in male rats.

Definition

ChEBI: The benzenesulfonate salt of amlodipine.

Manufacturing Process

2-[(2-Aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5- methoxycarbonyl-6-methyl-1,4-dihydropyridine (amlodipine) was prepared from 2-(phthalimidoaminoethoxy)acetoacetate, 2-chlorobenzaldehyde and methyl-3-aminocrotonate under refluxing in ethanol for 24 hours. The ketoester was prepared by the method of Troostwijk and Kellog (JCS Chem. Comm., 1977, p.932). Methyl-3-aminocrotonate can be prepared by known method. Phthalimido-amino-protecting group was removed using hydrazine hydrate in ethanol at the reflux temperature. Although amlodipine is effective as the free base, in practice it is best administered form of a salt of a pharmaceutically acceptable acid. Benzensulphonic salt of amlodipine was prepared as follows: Amlodipine base (65.6 g, 0.161 mols) was slurried in industrial methylated spirit (denatured alcohol, 326.4 ml) and cooled to 5°C. Benzensulphonic acid (26.2 g, 0.168 mols) was dissolved in industrial methylated spirit (65.6 ml) at 5°C and added to base. The resulting slurry was then granulated, filtered and washed with 2 volumes the same solvent (65.6 ml). The damp solid was slurred at 5°C for 1 hr in 327.6 ml industrial methylated spirit, filtered, washed with 2 volumes of the same solvent (65.6 ml) and dried under vacuum at 55°C for 24 hr. A yield of besylate salt of amlodipine 65 g.

Brand name

Norvasc (Pfizer);Istin.

Therapeutic Function

Antianginal, Antihypertensive

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. Amlodipine besylate is a calcium channel blocker, which inhibits the trans membrane influx of calcium ions into vascular smooth muscles and cardiac muscle. It belongs to the dihydropyridine family. It is used in combination with atorvastatin calcium to treat vasospastic angina, chronic stable angina, hypertension, in elevated serum triglyceride levels, primary dysbetalipoproteinemia.

Biological Activity

L-type calcium channel blocker that displays antihypertensive properties. Inhibits Ca 2+ -induced contractions in depolarized rat aorta (IC 50 = 1.9 nM) and displays vasoprotective effects in cardiovascular disease. Inhibits proliferation of human vascular smooth muscle cells and epidermoid carcinoma A431 cells (IC 50 = 25 μ M).

Biochem/physiol Actions

Amlodipine is an L-type calcium channel blocker. Amlodipine belongs to a class of cardiovascular drugs, which act at the voltage gated calcium channel of the CaV1, or L-type, class. Amlodipine also has antihypertensive and antianginal effects. Its activity resides mainly in the (-)-isomer. Amlodipine inhibits growth of human epidermoid carcinoma A431 cells and has antireproductive effects in male rats.

Veterinary Drugs and Treatments

Oral amlodipine appears to be a useful agent in the treatment of hypertension in cats and many consider it the drug of choice for this indication. In pharmacokinetic studies, amlodipine has decreased blood pressure in dogs with chronic renal disease, but its efficacy in treating hypertensive dogs has been disappointing. Hypertension in cats is usually secondary to other diseases (often renal failure or cardiac causes such as thyrotoxic cardiomyopathy or primary hypertrophic cardiomyopathy, etc.) and is most often seen in middle-aged or geriatric cats. These animals often present with acute clinical signs such as blindness, seizures, collapse or paresis. A cat is generally considered hypertensive if systolic blood pressure is >160 mmHg. Early reports indicate that if antihypertensive therapy is begun acutely, some vision may be restored in about 50% of cases of blindness secondary to hypertension.

references

[1] lee yj, park hh, koh sh, choi ny, lee ky. amlodipine besylate and amlodipine camsylate prevent cortical neuronal cell death induced by oxidative stress. j neurochem. 2011 dec;119(6):1262-70. doi: 10.1111/j.1471-4159.2011.07529.x. [2] yoshida j, ishibashi t, nishio m. antiproliferative effect of ca2+ channel blockers on human epidermoid carcinoma a431 cells. eur j pharmacol. 2003 jul 4;472(1-2):23-31. [3] henik ra, snyder ps, volk lm. treatment of systemic hypertension in cats with amlodipine besylate. j am anim hosp assoc. 1997 may-jun;33(3):226-34.

InChI:InChI=1/C20H25ClN2O5.CH4O3S/c1-4-28-20(25)18-15(11-27-10-9-22)23-12(2)16(19(24)26-3)17(18)13-7-5-6-8-14(13)21;1-5(2,3)4/h5-8,17,23H,4,9-11,22H2,1-3H3;1H3,(H,2,3,4)

Synthetic route

4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-[2-phthalimidoethoxymethyl]-1,4-dihydropyridine (88150-62-3) + benzenesulfonic acid (98-11-3) → amlodipine besylate (111470-99-6)

Conditions	Yield
Stage #1: 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-[2-phthalimidoethoxymethyl]-1,4-dihydropyridine With methylamine at 25℃; Large scale; Stage #2: benzenesulfonic acid In water at 30℃; Temperature; Large scale;	91.6%
Stage #1: 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-[2-phthalimidoethoxymethyl]-1,4-dihydropyridine With methylamine In water at 20 - 45℃; for 4.5h; Stage #2: benzenesulfonic acid In water at 20℃; for 4.5h; pH=1 - 2; Product distribution / selectivity;
Stage #1: 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-[2-phthalimidoethoxymethyl]-1,4-dihydropyridine With hydrazine In methanol; ethyl acetate at 34 - 37℃; for 0.05h; Inert atmosphere; Stage #2: benzenesulfonic acid In isopropyl alcohol at 5 - 30℃; for 2h;
Stage #1: 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-[2-phthalimidoethoxymethyl]-1,4-dihydropyridine With methylamine In dichloromethane at 25℃; for 4h; Stage #2: benzenesulfonic acid In dichloromethane at 25℃;	48 g

amlodipine formate (246852-08-4) + sodium phenylsulfonate (515-42-4) → amlodipine besylate (111470-99-6)

Conditions	Yield
In water at 5 - 20℃; for 0.333333h; Product distribution / selectivity;	90%

amlodipine chloroacetate (246852-11-9) + sodium phenylsulfonate (515-42-4) → amlodipine besylate (111470-99-6)

Conditions	Yield
Product distribution / selectivity;	89%

amlodipine Hydrochloride + sodium phenylsulfonate (515-42-4) → amlodipine besylate (111470-99-6)

Conditions	Yield
In water at 10 - 20℃; for 0.833333h; Product distribution / selectivity;	88%

2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) + benzenesulfonic acid (98-11-3) → amlodipine besylate (111470-99-6)

Conditions	Yield
In methanol; toluene at 0 - 20℃; for 2h;	87%
for 3h;
In isopropyl alcohol at 0 - 30℃; for 2 - 2.25h; Product distribution / selectivity;

amlodipine acetate (246852-10-8) + sodium phenylsulfonate (515-42-4) → amlodipine besylate (111470-99-6)

Conditions	Yield
In ethanol; water at 5 - 20℃; for 0.5h; Product distribution / selectivity;	83%

amlodipine nitrate (246852-13-1) + sodium phenylsulfonate (515-42-4) → amlodipine besylate (111470-99-6)

Conditions	Yield
Product distribution / selectivity;	83%

amlodipine mesylate + sodium phenylsulfonate (515-42-4) → amlodipine besylate (111470-99-6)

Conditions	Yield
Product distribution / selectivity;	81%

N-tritylamlodipine (156366-27-7) + benzenesulfonic acid (98-11-3) → amlodipine besylate (111470-99-6)

Conditions	Yield
With ethanol for 4.66667h; Heating / reflux;
With methanol at 45℃; Kinetics; Reagent/catalyst; Temperature; Large scale reaction;

N-tritylamlodipine (156366-27-7) + benzenesulfonic acid (98-11-3) → diethyl 2,6-bis[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate (331258-31-2) + dimethyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate (140171-66-0) + amlodipine besylate (111470-99-6)

Conditions	Yield
In methanol for 2h; Heating / reflux;
In methanol for 2h; Heating / reflux;

amlodipine hydrobromide (246852-09-5) + sodium phenylsulfonate (515-42-4) → amlodipine besylate (111470-99-6)

Conditions	Yield
In water for 0.333333h; Product distribution / selectivity;

ethyl 4-[2-(phthalimido)ethoxy]acetoacetate (88150-75-8) → amlodipine besylate (111470-99-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: piperidine / toluene / 35 - 65 °C / Large scale 2.1: acetic acid / 25 °C / Large scale 3.1: methylamine / 25 °C / Large scale 3.2: 30 °C / Large scale View Scheme

C27H29ClN2O5 + benzenesulfonic acid (98-11-3) → amlodipine besylate (111470-99-6)

Conditions	Yield
In cyclohexane; water at 0 - 60℃; Temperature;	2.51 g

methanesulfonic acid (75-75-2) + amlodipine besylate (111470-99-6) → amlodipine mesylate

Conditions	Yield
Stage #1: amlodipine besylate With sodium hydroxide In water; ethyl acetate for 0.666667h; Stage #2: methanesulfonic acid In water; ethyl acetate at 0 - 5℃;	90%

amlodipine besylate (111470-99-6) → 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9)

Conditions	Yield
With sodium hydroxide In water for 0.5h; Heating / reflux;	88.6%
With sodium hydroxide In tert-butyl methyl ether; water
With sodium hydroxide In methanol; water
With sodium hydroxide In water for 1h; Reagent/catalyst; Reflux;

bis(trichloromethyl) carbonate (32315-10-9) + (Z)-1-chloroethyl 4-hydroxybut-2-enyl carbonate (1345092-27-4) + amlodipine besylate (111470-99-6) → (Z)-3-ethyl 5-methyl 2-(15-chloro-6,13-dioxo-2,7,12,14-tetraoxa-5-azahexadec-9-enyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (1345092-43-4)

Conditions	Yield
Stage #1: bis(trichloromethyl) carbonate; amlodipine besylate With triethylamine In dichloromethane at 20℃; for 1.5h; Stage #2: (Z)-1-chloroethyl 4-hydroxybut-2-enyl carbonate In dichloromethane at 20℃; for 12h;	47%

toluene-4-sulfonic acid (104-15-4) + amlodipine besylate (111470-99-6) → amlodipine p-toluene sulfonate (852990-75-1)

Conditions	Yield
In methanol at 23℃; for 3h;

amlodipine besylate (111470-99-6) → amlodipine Hydrochloride

Conditions	Yield
With hydrogenchloride In methanol; water at 23℃; for 3h;

D-tartaric acid (147-71-7) + amlodipine besylate (111470-99-6) → (S)-amlodipine-hemi-D-tartrate

Conditions	Yield
Stage #1: amlodipine besylate With sodium hydroxide In tert-butyl methyl ether; water for 0.333333 - 0.5h; Stage #2: D-tartaric acid In tert-butyl methyl ether; ISOPROPYLAMIDE at 30 - 72℃; for 2.16667h; Resolution of racemate;
With sodium hydroxide In tert-butyl methyl ether; ISOPROPYLAMIDE; water at 20 - 72℃; for 5.66667 - 6.41667h; Resolution of racemate;

D-tartaric acid (147-71-7) + amlodipine besylate (111470-99-6) → S(-) amlodipine hemi D(-) tartarate

Conditions	Yield
Stage #1: amlodipine besylate With sodium hydroxide In tert-butyl methyl ether; water Stage #2: D-tartaric acid In tert-butyl methyl ether; N,N-dimethyl acetamide at 20 - 72℃;

heptakis(6-(2-hydroxypropyl))-β-cyclodextrin + amlodipine besylate (111470-99-6) → C6H6O3S*C20H25ClN2O5*C63H112O42

Conditions	Yield
In water at 20℃; for 24h; Darkness;

β‐cyclodextrin (7585-39-9) + amlodipine besylate (111470-99-6) → C6H6O3S*C20H25ClN2O5*C42H70O35 (156570-65-9)

Conditions	Yield
In water at 20℃; for 24h; Darkness;

amlodipine besylate (111470-99-6) → amlodipine besylate

Conditions	Yield
In potassium bromide for 192h; Irradiation;

amlodipine besylate (111470-99-6) → (-)-Amlodipine besylate (150566-71-5) + (+)-Amlodipine besylate (828247-64-9)

Conditions	Yield
With sodium dihydrogenphosphate; phosphoric acid In methanol; water pH=2.75; Reagent/catalyst; Ionic liquid; Resolution of racemate;

amlodipine besylate (111470-99-6) → [Mg(2-[(2-aminoethoxy)-methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridine dicarboxylic acid 3-ethyl-5-methyl esterbenzene sulfonate)(Cl)2(H2O)]

Conditions	Yield
With magnesium(II) chloride hexahydrate In methanol; water at 75℃; for 3h;

amlodipine besylate (111470-99-6) → [Sr(2-[(2-aminoethoxy)-methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridine dicarboxylic acid 3-ethyl-5-methyl esterbenzene sulfonate)(Cl)2(H2O)]*2H2O

Conditions	Yield
With strontium (III) chloride hexahydrate In methanol; water at 75℃; for 3h;

amlodipine besylate (111470-99-6) → [Ba(2-[(2-aminoethoxy)-methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridine dicarboxylic acid 3-ethyl-5-methyl esterbenzene sulfonate)(Cl)2(H2O)]

Conditions	Yield
With barium(II) chloride dihydrate In methanol; water at 75℃; for 3h;

amlodipine besylate (111470-99-6) → [Ca(2-[(2-aminoethoxy)-methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridine dicarboxylic acid 3-ethyl-5-methyl esterbenzene sulfonate)(Cl)2(H2O)]

Conditions	Yield
With water; calcium chloride In methanol at 75℃; for 3h;

palladium dichloride + amlodipine besylate (111470-99-6) → [Pd(2-[(2-aminoethoxy)-methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridine dicarboxylic acid 3-ethyl-5-methyl esterbenzene sulfonate)2]Cl2

Conditions	Yield
In methanol; water at 75℃; for 3h;

manganese(II) chloride tetrahydrate + water (7732-18-5) + amlodipine besylate (111470-99-6) → [Mn(2-[(2-aminoethoxy)-methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridine dicarboxylic acid 3-ethyl-5-methyl esterbenzene sulfonate)(Cl)2(H2O)]

Conditions	Yield
In methanol at 75℃; for 3h;

Upstream product

• 98-11-3 benzenesulfonic acid 
• 88150-62-3 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-[2-phthalimidoethoxymethyl]-1,4-dihydropyridine 
• 246852-13-1 amlodipine nitrate 
• 515-42-4 sodium phenylsulfonate 
• 246852-11-9 amlodipine chloroacetate 
• 246852-10-8 amlodipine acetate 
• 246852-09-5 amlodipine hydrobromide 
• 246852-08-4 amlodipine formate 
• 246852-12-0 amlodipine mesylate 
• 88150-42-9 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine 
• 156366-27-7 N-tritylamlodipine 
• 88150-75-8 ethyl 4-[2-(phthalimido)ethoxy]acetoacetate 

Downstream Products

• 88150-42-9 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine 
• 246852-12-0 amlodipine mesylate 
• 150566-71-5 (-)-Amlodipine besylate 
• 828247-64-9 (+)-Amlodipine besylate 

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Relevant articles and documents

A pharmaceutical model intermediate and its preparation method

The invention relates to a novel intermediate and its preparation method. The intermediate can be used for preparing amlodipine or pharmaceutically acceptable salts thereof; and amlodipine or salts thereof can be prepared through preparing the intermediate. The method is simple and safe to operate, avoids the use of flammable and explosive articles, and is in favor of the industrial mass production.

Synthesis process of amlodipine besylate

The invention discloses a synthesis process of amlodipine besylate, relates to the technical field of medicine synthesis and solves the problems of low product purity and poor product quality controllability of products prepared by the existing synthesis process. According to the synthesis process, phthalic anhydride is used as raw materials; the parameters of the synthesis process are controlled;the technical flow process is shortened; the synthesis cost is reduced; the product yield is as high as 91 percent; the purity of the prepared amlodipine besylate is as high as 99.5 percent. The self-made amlodipine besylate are used as raw materials for further preparing the amlodipine besylate tablets; the product cost is reduced; the product quality controllability is high.

Method for preparing amlodipine besylate tablet by one-pot method

The invention relates to a method for preparing an amlodipine besylate tablet by a one-pot method. The preparation method comprises the following steps: (1) taking phthaloyl amlodipine as a raw material, preparing an amlodipine solution in the presence of a solvent and a methylamine aqueous solution, wherein the reaction temperature is 10 to 50 DEG C, and the reaction time is 2 to 12 h; and (2) adding benzenesulfonic acid into the amlodipine solution in the step (1), stirring and mixing at 10 to 50 DEG C, and then separating to obtain the amlodipine besylate tablet. The method has the advantages that the amlodipine besylate tablet is prepared by the one-pot method, compared with the traditional preparation method of the amlodipine besylate tablet, the operation procedures are simple, a prepared amlodipine besylate tablet intermediate does not need to be separated, the loss of the amlodipine can be further reduced, the yield of the final amlodipine besylate tablet can be ensured, and the yield can be almost up to 100 percent; and meanwhile, by adopting the preparation method, impurities can be prevented from being introduced, the purity of the product can be improved, the purity can be up to 99.5 percent or above, the quality of the product is greatly ensured, and the industrial standard can be satisfied.

Using the new crystal form [...] and production of high-purity [...]

PROBLEM TO BE SOLVED: To provide a process for producing high-purity phthaloyl amlodipine for synthesis of an amlodipine besilate having excellent purity as a medicine.SOLUTION: Provided are TW-A type and TW-B type crystal forms of highly pure phthaloyl amlodipine. In powder X-ray diffraction, the TW-A type phthaloyl amlodipine has diffraction peaks at 2θ(°)=8.7±0.2, 11.0±0.2, 13.4±0.2, 15.7±0.2, and 24.6±0.2. In powder X-ray diffraction, the TW-B type phthaloyl amlodipine has diffraction peaks at 2θ(°)=6.6±0.2, 9.9±0.2, 11.1±0.2, 17.3±0.2, and 24.4±0.2.

AN IMPROVED PROCESS FOR THE PREPARATION OF AMLODIPINE FREE BASE AND ACID ADDITION SALTS THEREOF

Disclosed herein is an improved process for preparation of Amlodipine free base and acid addition salts thereof in good yield by deprotecting Phthaloyl Amlodipine using total concentration of 25% aqueous monomethyl amine in the reaction mixture and Amlodipine free base thus obtained is treated with suitable acids in aqueous medium to yield corresponding Amlodipine salts.

Amlodipine benzenesulfonate: A mechanistic investigation of its industrial preparation via detritylation of N-tritylamlodipine and related NMR studies

Kinetics and product analysis of detritylation of N-tritylamlodipine by benzenesulfonic acid in methanol, methanol-chloroform (volume ratio 9:1), ethanol, 2-propanol, and methanol/2-propanol (mole ratio 1:1) have been investigated by HPLC; amongst these reaction conditions are ones closely similar to those of one method of manufacturing amlodipine benzenesulfonate. Kinetics of detritylation of Ntritylamlodipine have also been investigated in methanol-d4 by 1H NMR spectroscopy and the agreement with the results by HPLC is good. The rate of detritylation increases with increasing concentrations of benzenesulfonic acid, and p-methoxy-substituents in the trityl group have been shown to lead to faster reactions. In methanol, the rate is hardly affected by 10 % (vol. fraction) chloroform. These studies relate to mechanistic investigations of acid-catalysed deaminations of methoxy-substituted tritylalkylamines, and Arrhenius activation parameters (Ea and A) are similar indicating a common generic mechanism. Acid-catalysed trans-esterification has been shown by HPLC to accompany detritylation in methanol, and attendant protium-deuterium exchange in the methyl at C6 by reversible acid-catalysed iminium ion formation in the 4-aryl-1,4-dihydropyridine moiety of both N-tritylamlodipine and amlodipine has been investigated in deuteriated methanol by 1H, 13C, and 15N NMR spectroscopy.

The effect of ion pairing on the skin permeation of amlodipine

The purpose of the present study was to evaluate the effect of ion pairing on the skin permeation of amlodipine. Amlodipine base (AM) was first prepared from amlodipine besilate (AM-B), then amlodipine adipate (AM-A), amlodipine oxalate (AM-O) and amlodipine maleate (AM-M) were prepared using AM and the corresponding organic acids. Differential scanning calorimetry (DSC) thermogram studies demonstrated the formation of complexes between AM and the various acids. In vitro percutaneous absorption of AM and its complexes was evaluated through excised rat skin using 2-chamber diffusion cells. The results showed that AM had the greatest steady-state flux and lowest permeability coefficient of the five compounds from the El system (ethanol : isopropyl myristate (IPM) = 2:8), and its four complexes all exhibited a lower flux and higher permeability coefficient than AM.

AN IMPROVED PROCESS FOR THE PREPARATION OF AMLODIPINE BESYLATE

The present invention provides a process for the preparation of amlodipine, which comprises purging of methylamine gas under stirring in phthaloyl amlodipine in presence of an organic solvent selected from the group consisting of toluene and isopropyl alcohol.

PROCESS FOR PREPARING AMLODIPINE

A process for preparing phthalimidoamlodipine, which is useful as an intermediate for the preparation of amlodipine and its salts.

A PROCESS FOR THE PREPARATION OF AMLODIPINE BENZENESULFONATE

The present invention relates to novel alkyl 2-(2-chlorobenzylidene)-4-(2- tritylaminoethoxy) acetoacetate, wherein alkyl represents C1C4 alkyl group, preferably ethyl 2-(2-chlorobenzylidene)-4-(2-tritylaminoethoxy) acetoacetate, as useful intermediate in the novel process for the preparation of amlodipine benzenesulfonate in high overall yield and high purity, containing substantially less then 0.1 Area % of 3,5-diethyl (±)-2-[(2-aminoethoxy)-methyl]-4-(2-chlorophenyl)-1,4- dihydro-6-methyl-3,5-pyridinedicarboxylate as the single remaining impurity. No other impurities are contained in obtained pure crystalline amlodipine benzenesulfonate. Preferably, 2-chlorobenzaldehyde is contacted with ethyl-4-[2-(N- tritylamino)ethoxy]acetoacetate in an organic solvent, preferably ethanol, to form ethyl-2-(2-chlorobenzylidene)-4-(2-tritylaminoethoxy) acetoacetate, which is converted without isolation from the reaction mixture, preferably with methyl (E)-3- aminocrotonate to form 3-ethyl 5-methyl (±)-2-[2-(N-tritylamino)ethoxymethyl]-4-(2- chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate ("tritylamlodipine"), which is converted without isolation from the reaction mixture with benzenesulfonic acid in an organic solvent, preferably ethanol, followed by isolation and purification of amlodipine benzenesulfonate. C1-C4 alkyl alcohols, especially methanol, ethanol, isopropanol and mixtures thereof, are used as an organic solvent. Amlodipine benzenesulfonate (besylate) is useful as antiishemic and antihypertensive agent.