88150-42-9

Basic information

• Product Name: Amlodipine
• Synonyms: 3,5-pyridinedicarboxylicacid,1,4-dihydro-2-((2-aminoethoxy)methyl)-4-(2-chlor;3-ethyl5-methylester;LOTREL;methyl ethyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate;AMLODIPINE;AMLODIPINE BASE;Amlodipin;besylate
• CAS NO: 88150-42-9
• Molecular Formula: C₂₀H₂₅ClN₂O₅
• Molecular Weight: 567.05
• EINECS: 1308068-626-2
• Product Categories: Active Pharmaceutical Ingredients;Dihydropyridine Class Chemicals;Intermediates & Fine Chemicals;Pharmaceuticals;Calcium channel;Aromatics;Dihydropyridine;Heterocycles;API;Free Base API;Norvasc
• Mol File: 88150-42-9.mol
• Article Data: 24

Chemical Properties

• Melting Point: 178-179°C
• Boiling Point: 527.2 °C at 760 mmHg
• Flash Point: 272.6 °C
• Appearance: Yellow solid
• Density: 1.227 g/cm³
• Storage Temp.: -20°C Freezer
• Solubility: Soluble in DMSO (up to 25 mg/ml), in DMF (up to 25 mg/ml) or in Ethanol (up to 25 mg/ml).
• PKA: pKa 8.6 (Uncertain)
• Water Solubility: 75.3 mg/L
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO, DMF, or ethanol may be stored at -20°C for up to 3 months.
• CAS DataBase Reference: Amlodipine(CAS DataBase Reference)
• NIST Chemistry Reference: Amlodipine(88150-42-9)
• EPA Substance Registry System: Amlodipine(88150-42-9)

Safety Data

• RTECS: US7968329
• HazardClass: IRRITANT
• Hazardous Substances Data: 88150-42-9(Hazardous Substances Data)

Usage

Description

Amlodipine is a dihydropyridine L-type calcium channel blocker that selectively inhibits calcium influx in cardiac and vascular smooth muscle. Acting as a vasodilator, amlodipine reduces blood pressure by relaxing the smooth muscle in the arterial wall, decreasing total peripheral resistance. It inhibits calcium-induced contractions in depolarized rat aorta with an IC50 value of 1.9 nM, displaying a slow rate of association and dissociation in isolated vascular and cardiac tissues. Amlodipine also demonstrates actions independent of L-type calcium channel blockade by regulating membrane fluidity and cholesterol deposition, stimulating nitric oxide production, acting as an antioxidant, and regulating matrix deposition in vitro and in vivo. Formulations containing amlodipine have been used in the treatment of hypertension.

Chemical Properties

Yellow Solid

Uses

Different sources of media describe the Uses of 88150-42-9 differently. You can refer to the following data:
1. A dihydropyridine calcium channel blocker; activity resides mainly in the (-)-isomer.
2. anti-hypertensive;calcium channel blocker
3. A deuterated dihydropyridine calcium channel blocker.;Application of Labeled APIs: Labeled Amlodipine, intended for use as an internal standard for the quantification of Amlodipine by GC- or LC-mass spectrometry.

Definition

ChEBI: A fully substituted dialkyl 1,4-dihydropyridine-3,5-dicarboxylate derivative, which is used for the treatment of hypertension, chronic stable angina and confirmed or suspected vasospastic angina.

Brand name

Norvasc (Pfizer).

General Description

Amlodipine, 2-[, for the treatment of hypertension. Amlodipineis also marketed as a combination therapy with atorvastatinunder the tradename Norvasc for the management of highcholesterol and high blood pressure.

Hazard

Human systemic effects.

Clinical Use

Calcium-channel blocker: Hypertension Angina prophylaxis

Safety Profile

Human systemic effects. Whenheated to decomposition it emits toxic vapors of NOx andCl-.

Drug interactions

Potentially hazardous interactions with other drugs Aminophylline and theophylline: possibly increased aminophylline and theophylline concentration. Anaesthetics: enhanced hypotensive effect. Antibacterials: metabolism possibly inhibited by clarithromycin, erythromycin and telithromycin. Antidepressants: enhanced hypotensive effect with MAOIs, concentration possibly reduced by St John’s wort. Antiepileptics: effects probably reduced by phenobarbital and primidone. Antifungals: negative inotropic effect possibly increased with itraconazole. Antihypertensives: enhanced hypotensive effect; increased risk of first dose hypotensive effect of postsynaptic alpha-blockers. Antivirals: concentration increased by telaprevir and possibly by ritonavir - reduce dose of amlodipine. Ciclosporin: ciclosporin concentration may be increased by up to 40%. Lipid lowering agents: possibly increased risk of myopathy - do not exceed 20 mg of simvastatin.1 Tacrolimus: possibly increased tacrolimus levels.

Metabolism

Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.

References

1) Mason et al. (2003), Novel vascular biology of third-generation L-type calcium channel antagonists: ancillary actions of amlodipine; Arterioscler. Thromb. Vasc. Biol., 23 2155 2) Asano et al. (2003), A calcium channel blocker activates both ecto-5(‘)-nucleotidase and NO synthase in HUVEC; Biochem. Biophys. Res. Commun., 311 625 3) Yu et al. (2003), Amlodipine modulates THP-1 cell adhesion to vascular endothelium via inhibition of protein kinase C signal transduction; Hypertension, 42 329 4) Zhou et al. (2004), Inhibition of oxidative stress and improvement of endothelial function by amlodipine in angiotensin II-infused rats; Am. J. Hypertension, 17 167 5) Ueda et al. (1993), A comparative assessment of the duration of action of amlodipine and nifedipine GITS in normotensive subjects; Br. J. Clin. Pharmacol., 36 561

InChI:InChI=1/C20H25ClN2O5/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/h5-8,17,23H,4,9-11,22H2,1-3H3

Synthetic route

2-(2-Amino-ethoxymethyl)-4-(2-chloro-phenyl)-6-methyl-pyridine-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester (113994-41-5) → 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9)

Conditions	Yield
With sodium cyanoborohydride; acetic acid at 15 - 25℃; for 2h; Reagent/catalyst; Temperature;	93.1%

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;

4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-[2-phthalimidoethoxymethyl]-1,4-dihydropyridine (88150-62-3) → 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9)

Conditions	Yield
With ethanol; methylamine at 28 - 32℃; for 17h;	87.2%
With hydrazine In methanol; toluene at 22 - 24℃; for 7h;	86.5%
With methylamine In ethanol for 3h; Ambient temperature;

2-(2-azidoethoxy)methyl-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-46-3) → 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9)

Conditions	Yield
With hydrogen; Lindlar's catalyst In ethanol for 1h; Ambient temperature;
With hydrogen; 5% Pd/CaCO3 In ethanol under 775.743 Torr;

ethyl (2-chloroaceto)acetate (638-07-3) → 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1.) NaH / 1.) THF, 1 h, 2.) THF, RT, overnight 2: 25 percent / propan-2-ol / 21 h / Heating 3: methylamine / ethanol / 3 h / Ambient temperature View Scheme
Multi-step reaction with 5 steps 1: 1.) NaH / 1.) THF, RT, 1 h, 2.) THF, RT, 16 h 2: NH4OAc / ethanol / 1 h / Heating 3: ethanol / 5 h / Heating 4: 16 h 5: H2 / 5percent Pd/CaCO3 / ethanol / 1 h / Ambient temperature View Scheme

ethyl 4-(2-azidoethoxy)acetoacetate (88150-45-2) → 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: NH4OAc / ethanol / 1 h / Heating 2: ethanol / 5 h / Heating 3: 16 h 4: H2 / 5percent Pd/CaCO3 / ethanol / 1 h / Ambient temperature View Scheme

ethyl 4-[2-(phthalimido)ethoxy]acetoacetate (88150-75-8) → 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 25 percent / propan-2-ol / 21 h / Heating 2: methylamine / ethanol / 3 h / Ambient temperature View Scheme

(E)-3-Amino-4-(2-azido-ethoxy)-but-2-enoic acid ethyl ester → 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: ethanol / 5 h / Heating 2: 16 h 3: H2 / 5percent Pd/CaCO3 / ethanol / 1 h / Ambient temperature View Scheme

2-(2-azidoethoxy)methyl-5-carboxy-4-(2-chlorophenyl)-3-ethoxycarbonyl-6-methyl-1,4-dihydropyridine (120289-15-8) → 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 16 h 2: H2 / 5percent Pd/CaCO3 / ethanol / 1 h / Ambient temperature View Scheme

4-(2-chloro-phenyl)-2-(2-hydroxyimino-ethoxymethyl)-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester → 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9)

Conditions	Yield
With ammonium formate; palladium dihydroxide In methanol; dichloromethane

(R)-2-[(2-aminoethoxy)methyl]4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid 3-ethyl 5-methyl ester (103129-81-3) → 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: calcium hypochlorite / ethyl acetate; water / 20 - 30 °C 2: acetic acid; sodium cyanoborohydride / 2 h / 15 - 25 °C View Scheme

2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) + L-Pyroglutamic acid (98-79-3) → amlodipine (R)-(+)-pyroglutamate (663180-17-4)

Conditions	Yield
In ethanol at 5 - 20℃; for 1h;	97.1%

malonic acid (141-82-2) + 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) → amlodipine malonate salt (851447-21-7)

Conditions	Yield
In ethanol at 5 - 20℃; for 1h;	96.8%

Hippuric Acid (495-69-2) + 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) → amlodipine hipurate salt (851447-18-2)

Conditions	Yield
In ethanol at 5 - 20℃; for 1h;	96.8%

L-Tartaric acid (87-69-4) + 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) + N,N-dimethyl-formamide (68-12-2, 33513-42-7) → (S)-amlodipine-L-hemitartrate dimethylformamide solvate + (R)-amlodipine-L-hemitartrate dimethylformamide solvate + (R)-2-[(2-aminoethoxy)methyl]4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid 3-ethyl 5-methyl ester (103129-81-3)

Conditions	Yield
at 20℃; for 4.5h; Product distribution / selectivity;	A 96.25% B n/a C n/a

methanesulfonic acid (75-75-2) + 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) → amlodipine mesylate

Conditions	Yield
In water; ethyl acetate at 25℃; Temperature; Solvent;	96%
In methanol; toluene at 0 - 5℃; for 15h;	90%
In ethyl acetate at 20℃; for 1h;	3.32%
In ethyl acetate at 0 - 25℃; for 2 - 2.25h; Product distribution / selectivity;

(S)-Malic acid (97-67-6) + 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) → amlodipine hemi-L-malate salt

Conditions	Yield
In ethanol at 5 - 20℃; for 1h;	96%

2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) + L-Pyroglutamic acid (98-79-3) → amlodipine (S)-(-)-pyroglutamate (663180-18-5)

Conditions	Yield
In ethyl acetate at 25℃; for 1h;	95.3%

2-methylglutaric acid (18069-17-5) + 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) → amlodipine hemi-2-methyl glutarate salt

Conditions	Yield
In diethyl ether; tert-butyl alcohol at 5 - 20℃; for 4h;	95%

2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) → 2-(2-azidoethoxy)methyl-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-46-3)

Conditions	Yield
With fluorosulfonyl azide; potassium hydrogencarbonate In tert-butyl methyl ether; water; N,N-dimethyl-formamide at 20℃; for 0.0833333h; Solvent;	95%

2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) + dimethyl N-cyanodithioiminocarbonate (10191-60-3) → N-<2-<<4-(2-Chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydropyrid-2-yl>methoxy>ethyl>-N'-cyano-S-methylisothiourea (93117-86-3)

Conditions	Yield
In isopropyl alcohol for 4h; Ambient temperature;	94%

2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) + tetramethylammonium trifluoromethanethiolate → 3-ethyl 5-methyl 4-(2-chlorophenyl)-2-((2-isothiocyanatoethoxy)-methyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate

Conditions	Yield
With triethylamine In dichloromethane at 20℃; for 0.25h;	94%

2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) + acetic acid (64-19-7) → 2-(2-aminoethoxy)methyl-3-ethoxycarbonyl-4-(o-chlorophenyl)-5-methoxycarbonyl-6-methylpyridine acetate

Conditions	Yield
With lead(IV) acetate In dichloromethane at 20℃; for 0.75h;	92%

4-hydroxyphenylacetate (156-38-7) + 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) → amlodipine p-hydroxyphenylacetate (652969-06-7)

Conditions	Yield
In ethyl acetate at 23℃; for 3h;	92%
In ethyl acetate at 23℃; for 3h;	92%

2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) + Diphenylphosphine oxide (4559-70-0) → C32H34ClN2O6P

Conditions	Yield
With tert.-butylhydroperoxide; zinc(II) iodide In hexane; dichloromethane at 25℃; for 1h;	92%

2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) + maleic acid (110-16-7) → (RS)-amlodipine maleate (88150-47-4)

Conditions	Yield
In methanol; toluene at 21 - 24℃; for 1h;	91.2%
In methanol; isopropyl alcohol at 25 - 30℃; for 1.5 - 1.75h; Product distribution / selectivity;
In methanol at 50℃;

3,5-dimethylbenzenesulfinic acid (18023-22-8) + 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) → amlodipine meta-xylenesulfonate salt

Conditions	Yield
In ethanol at 5 - 20℃; for 1h;	91.1%

Adipic acid (124-04-9) + 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) → amlodipine adipate (526216-43-3)

Conditions	Yield
In methanol at 7 - 23℃; for 3h;	91%
In methanol at 7 - 23℃; for 3h;	91%
In methanol at 50℃;

2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) → amlodipine (103129-82-4)

Conditions	Yield
Stage #1: 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine With D-(+)-camphoric acid In isopropyl alcohol at 20℃; for 12.5h; Stage #2: With sodium hydroxide In dichloromethane; water for 1h; Reagent/catalyst;	90.5%
With D-tartaric acid In dimethyl sulfoxide; acetone at 20 - 60℃; for 1.5h; Reagent/catalyst; Solvent;	45.2%
Stage #1: 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine With L-Tartaric acid In ISOPROPYLAMIDE at 5℃; for 2h; Resolution of racemate; Stage #2: With sodium hydroxide In dichloromethane; water for 0.666667h;	n/a
Multi-step reaction with 2 steps 1: water; iso-butanol / 1 h / 50 °C 2: sodium hydroxide / dichloromethane; water / pH 9 View Scheme

ethanesulfonic acid (594-45-6) + 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) → amlodipine ethanesulfonate (652970-52-0)

Conditions	Yield
In methanol at 23℃; for 2h;	90%

(1R)-(-)-10-camphorsulfonic acid + 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) → amlodipine (1R)-(-)-10-camphorsulfonate

Conditions	Yield
In methanol at 7 - 22℃; for 3h;	90%

2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) + (1S)-(+)-10-camphorsulfonic acid → amlodipine (1S)-(+)-10-camphorsulfonate

Conditions	Yield
In methanol at 7 - 23℃; for 3h;	90%

2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) + benzonitrile (100-47-0) → 3-ethyl5-methyl2-((2-(benzylamino)ethoxy)methyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate

Conditions	Yield
With borane-ammonia complex; C16H29Cl2CoN2P at 20℃; for 13h; Schlenk technique; Inert atmosphere; chemoselective reaction;	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;

cyclohexylsulfamic acid (100-88-9) + 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) → amlodipine cyclamate (745013-02-9)

Conditions	Yield
In ethanol; ethyl acetate at 20℃; for 4h;	87%
In ethanol; isopropyl alcohol at 0℃; for 4h;	86%
In methanol; acetonitrile at 20℃; for 4h;	85%
In isopropyl alcohol at 0℃; for 4h;	82%

camphor-10-sulfonic acid (76-26-6, 3144-16-9, 5872-08-2, 35963-20-3) + 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) → amlodipine camsylate

Conditions	Yield
In methanol at 10℃; for 2h;	86.8%

2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) + Glycine ethyl ester isocyanate (2949-22-6) → 1-<2-<<4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydropyrid-2-yl>methoxy>ethyl>-3-<(ethoxycarbonyl)methyl>urea (97290-23-8)

Conditions	Yield
In acetonitrile for 2.5h; Heating;	86%

3-methyl glutaric acid (626-51-7) + 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (88150-42-9) → amlodipine hemi-3-methyl glutarate salt

Conditions	Yield
In diethyl ether; tert-butyl alcohol at 5 - 20℃; for 4h;	85.7%

Upstream product

• 638-07-3 ethyl (2-chloroaceto)acetate 
• 111470-99-6 amlodipine besylate 
• 113994-41-5 2-(2-Amino-ethoxymethyl)-4-(2-chloro-phenyl)-6-methyl-pyridine-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester 
• 103129-81-3 (R)-2-[(2-aminoethoxy)methyl]4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid 3-ethyl 5-methyl ester 
• 120289-15-8 2-(2-azidoethoxy)methyl-5-carboxy-4-(2-chlorophenyl)-3-ethoxycarbonyl-6-methyl-1,4-dihydropyridine 
• 88150-75-8 ethyl 4-[2-(phthalimido)ethoxy]acetoacetate 
• 88150-45-2 ethyl 4-(2-azidoethoxy)acetoacetate 
• 88150-62-3 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-[2-phthalimidoethoxymethyl]-1,4-dihydropyridine 
• 88150-46-3 2-(2-azidoethoxy)methyl-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine 

Downstream Products

• 88150-57-6 ethyl 2-<<2-<<4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydropyrid-2-yl>methoxy>ethyl>amino>acetate 
• 113994-41-5 2-(2-Amino-ethoxymethyl)-4-(2-chloro-phenyl)-6-methyl-pyridine-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester 
• 852990-75-1 amlodipine p-toluene sulfonate 
• 652969-06-7 amlodipine p-hydroxyphenylacetate 
• 526216-43-3 amlodipine adipate 
• 93849-15-1 4-(2-chlorophenyl)-3-ethoxycarbonyl-2-{2-[N-(1-imidazolylcarbonyl)amino]ethoxymethyl}-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine 
• 93848-71-6 1-<2-<<4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydropyrid-2-yl>methoxy>ethyl>sulfamide 
• 93117-86-3 N-{2-[(4-{2-Chlorophenyl}-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl)methoxy]ethyl}-N'-cyano-S-methyl-isothiourea 
• 93118-36-6 4-(2-Chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-[2-(2-thiazolin-2-ylamino)ethoxymethyl]-1,4-dihydropyridine 

Relevant articles and documents

Light-Induced Formation/Scission of C-N, C-O, and C-S Bonds Enables Switchable Stability/Degradability in Covalent Systems

The manipulation of covalent bonds could be directed toward degradable, recyclable, and sustainable materials. However, there is an intrinsic conflict between properties of stability and degradability. Here we report light-controlled formation/scission of three types of covalent bonds (C-N, C-O, and C-S) through photoswitching between equilibrium and nonequilibrium states of dynamic covalent systems, achieving dual benefits of photoaddressable stability and cleavability. The photocyclization of dithienylethene fused aldehyde ring-chain tautomers turns on the reactivity, incorporating/releasing amines, alcohols, and thiols reversibly with high efficiency, respectively. Upon photocycloreversion the system is shifted to kinetically locked out-of-equilibrium form, enabling remarkable robustness of covalent assemblies. Reaction coupling allows remote and directional control of a diverse range of equilibria and further broadens the scope. Through locking and unlocking covalent linkages with light when needed, the utility is demonstrated with capture/release of bioactive molecules, modification of surfaces, and creation of polymers exhibiting tailored stability and degradability/recyclability. The versatile toolbox for photoswitchable dynamic covalent reactions to toggle matters on and off should be appealing to many endeavors.

Two validated stability-indicating chromatographic methods for the separation of two anti-hypertensive combinations in the presence of their degradation products or impurities

Two RP-HPLC methods were developed, optimized, and validated for the determination of two different anti-hypertensive combinations in the presence of their degradation products or impurities and in their pharmaceutical formulations. The first mixture is Ramipril (RAM) in combination with Amlodipine besylate (AML) [mixture I], while the second one is a combination of Ramipril (RAM), Atorvastatin (ATV), and Aspirin (ASP) [mixture II].The proposed combinations were successfully separated on X-bridge C18column (250 × 4.6?mm i.d, 5?μm p.s.), using a mobile phase of 0.05?M phosphate buffer-acetonitrile-THF (60:40:0.1% by volume) pH 2.5 and an isocratic mobile phase formed of acetonitrile-0.05?M phosphate buffer-THF (60:40:0.1% by volume) pH 2.5 for mixture (I) and (II) at a flow rate of 1?mL/min and 1.2?mL/min, respectively. The compromising components of the mixtures were detected at 218?nm. For the best separation of the mentioned components different parameters were examined and optimized. The two suggested methods were validated in compliance with the ICH guidelines and were successfully applied for the quantification of the cited components in presence of their obtained degradation products as well as in their commercial pharmaceutical formulations. For both methods the obtained results were statistically analyzed and compared to those of the official and reported methods; using Student’s t test and F test showing no significant difference with high accuracy and good precision.

ANTIHYPERTENSIVE THERAPY

A new use of darusentan is provided in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy with one or more drugs. The composition comprises darusentan in an amount providing a therapeutically effective daily dose; wherein (a) the composition is orally deliverable and/or (b) the daily dose of darusentan is effective to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures. Further provided is a new use of darusentan in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy, wherein the composition is administered adjunctively with at least one diuretic and at least one antihypertensive drug selected from ACE inhibitors, angiotensin II receptor blockers, beta-adrenergic receptor blockers and calcium channel blockers.