59-98-3

Basic information

• Product Name: Tolazoline
• Synonyms: TIMTEC-BB SBB003964;TOLAZOLINE;2-BENZYL-2-IMIDAZOLINE;LABOTEST-BB LT00772362;2-benzyl-2-imidazolin;2-Benzyl-4,5-dihydro-1H-imidazole;2-Benzyl-4,5-imidazoline;2-Benzyl-4,5-imidazoline hydrochloride
• CAS NO: 59-98-3
• Molecular Formula: C₁₀H₁₂N₂
• Molecular Weight: 160.22
• EINECS: 200-448-9
• Mol File: 59-98-3.mol

Chemical Properties

• Melting Point: 66-69 °C(lit.)
• Boiling Point: 188°C/20mmHg(lit.)
• Flash Point: 158.3°C
• Appearance: /
• Density: 1.0849 (rough estimate)
• Refractive Index: 1.6392 (estimate)
• Storage Temp.: 2-8°C
• Solubility: alcohol: freely soluble
• PKA: pKa 10.3(H2O t undefined I = 0.1) (Uncertain)
• Merck: 14,9506
• CAS DataBase Reference: Tolazoline(CAS DataBase Reference)
• NIST Chemistry Reference: Tolazoline(59-98-3)
• EPA Substance Registry System: Tolazoline(59-98-3)

Safety Data

• Hazard Codes: Xn
• Statements: 20/21/22-36/37/38
• Safety Statements: 26-28-36/37/39-45
• WGK Germany: 3
• RTECS: NJ1925000
• Hazardous Substances Data: 59-98-3(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Tolazoline is used as a vasodilator for treating stable forms of pulmonary hypertension in newborns. It helps to improve blood flow and oxygenation in cases where systemic arterial oxygenation cannot be achieved in the usual manner under careful observation of professionals.
Used in Chemical Synthesis:
Tolazoline serves as a reactant for the synthesis of imidazoline-containing drugs. Imidazoline drugs have a wide range of applications in the pharmaceutical industry, including the treatment of hypertension, heart failure, and various other cardiovascular conditions. The synthesis of these drugs often involves the use of tolazoline as a key intermediate compound, highlighting its importance in the development of new and effective medications.

Therapeutic Function

Vasodilator

Pharmacology

Tolazoline is a weak, reversible α-adrenoblocker that lowers resistance of peripheral blood vessels and elevates venous capacity. However, it also exhibits β-adrenomimetic activity, which consists of the stimulation of cardiac work and is manifest as tachycardia, cholinergic activity, which consists of stimulation of the gastrointestinal tract, and histamine-like activity, which consists of stimulation of gastric secretion.

Safety Profile

Poison by ingestion,intraperitoneal, and intravenous routes. Mutation data reported. When heated to decomposition it emits toxicfumes of NOx.

Synthesis

Tolazoline, 2-benzyl-2-imidazoline (12.2.7), is synthesized by the heterocyclation of the ethyl ester of iminophenzylacetic acid with ethylendiamine (12.2.6), which forms the desired product (12.2.7) [32–35]. The structure of tolazoline is strikingly similar to α-adrenergic agonists, which are antiedema sympathomimetics.

InChI:InChI=1/C10H12N2/c1-2-4-9(5-3-1)8-10-11-6-7-12-10/h1-5H,6-8H2,(H,11,12)

Upstream product

• 5467-51-6 N-(cyanomethyl)-2-phenylacetamide 
• 140-29-4 phenylacetonitrile 
• 141-43-5 ethanolamine 
• 107-15-3 ethylenediamine 
• 103-81-1 Benzeneacetamide 
• 106-93-4 ethylene dibromide 
• 101-97-3 Ethyl 2-phenylethanoate 
• 103-82-2 phenylacetic acid 
• 4971-77-1 ethyl 2-phenylethanimidoate 
• 24433-82-7 2-phenyl-acetimidic acid methyl ester 
• 111512-93-7 1-(phenylethynyl)aziridine 
• 5442-34-2 ethyl 2-phenylacetimidate hydrochloride 
• 7436-90-0 2,2-dibromostyrene 
• 122-78-1 phenylacetaldehyde 

Downstream Products

• 63226-76-6 1-acetylamino-2-(2-phenyl-acetylamino)-ethane 
• 102754-28-9 1,3-dibenzoyl-2-benzylidene-imidazolidine 
• 63224-23-7 N-[2-(dimethylamino)ethyl]-2-phenylacetamide 
• 14700-62-0 2-benzyl-1H-imidazole 
• 15070-17-4 N-(2-aminoethyl)-2-phenylacetamide 
• 73775-59-4 1,2-Dibenzyl-2-imidazoline 
• 73775-60-7 1-β-Diethylaminoethyl-2-benzyl-2-imidazoline 
• 65248-65-9 2-benzyl-1-methyl-4,5-dihydro-1H-imidazole 
• 95467-25-7 4,5-Dihydro-1,3-dimethyl-2-(phenylmethyl)imidazolium-iodid 
• 122-78-1 phenylacetaldehyde 
• 216434-79-6 N-Nitrotolazoline 
• 292862-97-6 1-(4,5-Dihydro-1H-imidazol-2-yl)-1-phenyl-1-(3-nitro-2-thienyl)methanol 

Relevant articles and documents

Synthesis of tetrazoles, triazoles, and imidazolines catalyzed by magnetic silica spheres grafted acid

The magnetically separable catalysts are used in the synthesis of N-containing heterocycles, including tetrazoles, triazoles, and imidazolines. The magnetic silica sphere grafted sulfonic acid (MSS-SO3H) is suitable for the synthesis of 1,2,3-triazole via the cycloaddition of nitroalkene with NaN3, whereas the zinc-modified silica sphere catalyst (MSS-SO3Zn) is more suitable for the synthesis of tetrazoles. The MSS-SO3Zn catalyst also works well for the synthesis of 2-substituted imidazoline via the condensation of nitriles with ethylenediamine. Both of the MSS-SO3H and MSS-SO3Zn catalysts can be recovered easily by a magnet, and they can be reused without further tedious activation.

Semi-empirical computation on mechanism of imidazolines and benzimidazoles synthesis and their QSAR studies

A green, mild and anaerobic synthesis of imidazolines and benzimidazoles from aldehydes and diamines using I2/KI/K2CO3/H2O system has been investigated by semi-empirical methods. The observed efficient direction of the above synthesis has been modeled from a comparison of the energies of four possible transition states arising from mono and di additions of iodines in the configured molecules. In the reaction I1 B is the most favorable transition state [TS] which is shown to be 20 Kcal/mol by PM3 analyses. The resulting trends of relative transition states energies are in excellent agreement with the experimental observations. Also, the bond order, bond length, heat of formation is in good agreement to the formation of product B. In order to establish the suitable mechanism of the reaction a quantitative structure activity relationship analysis has been made using hydrophobicity as the molecular descriptor. In this analysis the values of refractivity, polarizability, hydration energy, electron affinity, ionization potential and dipole moment of the compounds have been correlated with their hydrophobicity which has been taken as the molecular property.

Optimisation of imidazole compounds as selective TAAR1 agonists: Discovery of RO5073012

A series of imidazole compounds has been identified which affords potent and selective partial and full agonists of the TAAR1 receptor. Starting from 2-benzyl-imidazoline screening hits, a series of structurally related 2-benzyl- and 4-benzyl-imidazoles was investigated first, but it proved highly challenging to obtain compounds having sufficient selectivity against the adrenergic alpha 2 receptor. This issue could be successfully addressed by modification of the linker region and SAR exploration led to the discovery of highly selective isopropyl-substituted 4-aminomethyl-imidazole compounds. The work culminated in the identification of the selective TAAR1 partial agonist RO5073012 (4-chlorophenyl)-(1H-imidazol-4-ylmethyl)-isopropyl-amine, 24), which has a good pharmacokinetic profile after oral administration in rodents. RO5073012 has been found to be active in a behavioural rat model which is considered indicative for schizophrenia.

CuCl-catalyzed radical cyclisation of N-α-perchloroacyl-ketene-N,S- acetals: A new way to prepare disubstituted maleic anhydrides

The copper-catalyzed radical cyclization (RC) of N-α-perchloroacyl cyclic ketene-N,X(X=O, NR, S)-acetals was studied. While the RC of N-acyl ketene-N,O-acetals was unsuccessful, the 5-endo cyclization of the other ketene acetals provided much better results, with the following order of cyclization efficiency: hexa-atomic cyclic ketene-N,NR-acetalspenta-atomic cyclic ketene-N,S-acetalshexa-atomic cyclic ketene-N,S-acetals. Invariably the catalytic cycle begins with the formation of a carbamoyl methyl radical. This leads to a cascade of reactions, including a radical polar crossover step, which ends with the formation of the maleimide nucleus, or precursors of this. Products from the RC of the hexa-atomic cyclic ketene-N,S-acetals, were efficiently transformed into disubstituted maleic anhydrides.

THERAPY FOR COMPLICATIONS OF DIABETES

A method for enhancing glycemic control and/or insulin sensitivity in a human subject having diabetic nephropathy and/or metabolic syndrome comprises administering to the subject a selective endothelin A (ETA) receptor antagonist in a glycemic control and/or insulin sensitivity enhancing effective amount. A method for treating a complex of comorbidities in an elderly diabetic human subject comprises administering to the subject a selective ETA receptor antagonist in combination or as adjunctive therapy with at least one additional agent that is (i) other than a selective ETA receptor antagonist and (ii) effective in treatment of diabetes and/or at least one of said comorbidities other than hypertension. A therapeutic combination useful in such a method comprises a selective ETA receptor antagonist and at least one antidiabetic, anti-obesity or antidyslipidemic agent other than a selective ETA receptor antagonist.

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.

N-nitrosotolazoline: Decomposition studies of a typical N-nitrosoimidazoline

N-Nitrosotolazoline (N-nitroso-2-benzylimidazoline), a N-nitrosated drug typical of N-nitrosoimidazolines, reacts readily with aqueous acid, nitrous acid, or N-acetylcysteine to produce highly electrophilic diazonium ions capable of alkylating cellular nucleophiles. The kinetics and mechanism of the acidic hydrolytic decomposition of N-nitrosotolazoline have been determined in mineral acids and buffers. The mechanism of decomposition in acidic buffer is proposed to involve the rapid reversible protonation of the imino nitrogen atom followed by slow general base-catalyzed addition of H2O to the 2-carbon of the imidazoline ring to give a tetrahedral intermediate, which is also a α-hydroxynitrosamine. Rapid decomposition of this species gives rise to the diazonium from which the products are derived by nucleophilic attack, elimination, and rearrangement. The proposed mechanism is supported by the observations of general acid catalysis, a negligible deuterium solvent kinetic isotope effect (kH/kD - 1.15) and ΔS≠ = -34 eu. In phosphate buffer at 30°C, the half-lives of N-nitrosotolazoline range from 5 min at pH 3.5 to 4 h at pH 6. The main reaction product of the hydrolytic decomposition is N-(2-hydroxyethyl)phenylacetamide. This and other products are consistent with the formation of a reactive diazonium ion intermediate. N-Nitrosotolazoline nitrosates 50 times more rapidly than tolazoline and results in a set of products derived from reactive diazonium ions but different from those produced from the hydrolytic decomposition of the substrate. N-Acetylcysteine increases the decomposition rate of N-nitrosotolazoline by 25 times at pH 7 and results in both N-denitrosation and induced decomposition to produce electrophiles. These data suggest that N-nitrosotolazoline shares the chemical properties of many known direct-acting mutagens and carcinogens.

Method for treating resistant hypertension

A method is provided for lowering blood pressure in a patient having clinically diagnosed resistant hypertension. The method comprises administering darusentan to the patient adjunctively with a baseline antihypertensive regimen that comprises administration of at least one diuretic and at least two antihypertensive drugs selected from at least two of (a) ACE inhibitors and angiotensin II receptor blockers, (b) beta-adrenergic receptor blockers and (c) calcium channel blockers. The darusentan is orally administered at a dose and frequency effective, in combination with the baseline regimen, 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.

An efficient preparation of 2-imidazolines and imidazoles from aldehydes with molecular iodine and (diacetoxyiodo)benzene

2-Imidazolines were easily prepared in quite good yields from the reaction of aldehydes and ethylenediamine with molecular iodine in the presence of potassium carbonate. Moreover, 2-imidazolines obtained were smoothly oxidized to the corresponding imidazoles in good yields using (diacetoxyiodo)benzene at room temperature. Georg Thieme Verlag Stuttgart.

An efficient and one-pot synthesis of imidazolines and benzimidazoles via anaerobic oxidation of carbon-nitrogen bonds in water

The system, I2/KI/K2CO3/H2O, oxidizes carbon-nitrogen bonds for the synthesis of imidazolines and benzimidazoles from aldehydes and diamines under anaerobic conditions in water at 90°C with excellent yields. The process is green, mild and inexpensive.