50679-08-8

Basic information

• Product Name: Terfenadine
• Synonyms: ALPHA-[4-(1,1-DIMETHYLETHYL)PHENYL]-4-(HYDROXYDIPHENYLMETHYL)-1-PIPERIDINEBUTANOL;TERFENADINE;1-(4-tert-butylphenyl)-4-(4-(alpha-hydroxybenzhydryl)piperidino)-butan-1-ol;1-(4-tert-Butylphenyl)-4-(4-[hydroxy(diphenyl)methyl]-1-piperidinyl)-1-butanol;1-(p-tert-butylphenyl)-4-(4’-(alpha-hydroxydiphenylmethyl)-1’-piperidyl)-butan;1-Piperidinebutanol, alpha-[4-(1,1-dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-;1-piperidinebutanol,alpha-(4-(1,1-dimethylethyl)phenyl)-4-(hydroxydiphenylmeth;Aldaban
• CAS NO: 50679-08-8
• Molecular Formula: C₃₂H₄₁NO₂
• Molecular Weight: 471.67
• EINECS: 256-710-8
• Product Categories: Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Histamine receptor;Ion Channels;ALAVERT
• Mol File: 50679-08-8.mol

Chemical Properties

• Melting Point: 145-152 °C
• Boiling Point: 572.76°C (rough estimate)
• Flash Point: 306.9 °C
• Appearance: white solid
• Density: 1.0488 (rough estimate)
• Vapor Pressure: 1.41E-16mmHg at 25°C
• Refractive Index: 1.6310 (estimate)
• Storage Temp.: 2-8°C
• Solubility: chloroform: soluble250 mg plus 5 ml of solvent, clear to very sl
• PKA: pKa 9.21(H2O t = 25 I = 0.025) (Uncertain)
• Water Solubility: 0.001 g/100 mL (30 ºC)
• CAS DataBase Reference: Terfenadine(CAS DataBase Reference)
• NIST Chemistry Reference: Terfenadine(50679-08-8)
• EPA Substance Registry System: Terfenadine(50679-08-8)

Safety Data

• Safety Statements: 24/25
• WGK Germany: 2
• RTECS: TM4969000
• Hazardous Substances Data: 50679-08-8(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Terfenadine is used as an antihistaminic agent for treating symptoms associated with seasonal allergic rhinitis and conjunctivitis. It helps in providing relief from angioneurotic edema and allergic skin reactions, as well as being a component of complex therapy for bronchial asthma.
Used in Research and Development:
In the field of research, Terfenadine has been utilized to study the role of histamine in itch related to proteinase-activated receptors (PARs) in mice. Additionally, it has been employed to block histamine receptor type 1, aiding in the investigation of the pathogenesis of 2,4-dinitrobenzene sulfonic acid (DNBS)-induced ulcerative colitis in rats.

Originator

Histafen,Berk

Manufacturing Process

A mixture of 107 g (0.4 mole) of α,α-diphenyl-4-piperidinemethanol, 105 g (0.44 mole) of 4'-tert-butyl-4-chlorobutyrophenone, 70 g (0.7 mole) of potassium bicarbonate, and a small amount of potassium iodide in 600 ml of toluene was refluxed and stirred for 2.5 days then filtered. The filtrate was treated with charcoal, filtered through celite then treated with ethereal HCl. The resulting solid was recrystallized from methanol and isopropyl alcohol to give the 4'-tert-butyl-4-[4-(α-hydroxy-α-phenylbenzyl)piperidino]- butyrophenone hydrochloride, melting point 234°-235°C.To a mixture of 4.2 g (0.0083 mole) of 4'-tert-butyl-4-[4-(α-hydroxy-α- phenylbenzyl)piperidino]-butyrophenone hydrochloride and 0.54 g (0.01 mole) of sodium methoxide in 25 ml of methanol is added 2.16 g (0.04 mole) of potassium borohydride. The reaction mixture is stirred overnight, diluted with water and the methanol removed under reduced pressure. The remaining material is extracted with chloroform, washed with water, dried over magnesium sulfate and filtered. The filtrate is concentrated, and the residue is recrystallized from acetone-water to give 4-[α-(p-tert-butylphenyl)-α- hydroxybenzyl]-α-phenyl-1-piperidinebutanol, melting point 161°-163°C.

Therapeutic Function

Antihistaminic, Bronchodilator

World Health Organization (WHO)

The first clinically interesting histamine H-receptor1 antagonists were introduced in the late 1940s and early 1950s. Several H-antihistaminics have a similar cardiac effect to that seen with astemizole1 and terfenadine. Serious cardiovascular adverse reactions have been reported when used concomitantly with imidazole antifungals and macrolide antibiotics. See also under astemizole.

Biological Activity

Histamine H 1 receptor antagonist. Also blocks hERG and K ATP channels (IC 50 values are 204 nM and 1.2 μ M respectively). Inhibits the delayed rectifier K + current (I Kr ) in guinea pig ventricular myocytes (IC 50 = 50 nM). Activity prolongs QT and induces Torsades de pointes (TdP); cardiotoxic in vivo .

Biochem/physiol Actions

Non-sedating second generation H1 histamine receptor antagonist. Mainly metabolized by Cyp3A4, 5, 7. Inhibits CYP2C8.

Pharmacology

Terfenadine not only differs from the other antihistamine drugs in its chemical structure, but also in that its action begins within 1–2 h and last approximately 12 h, reaching its peak of action in 3–4 h.

Synthesis

Terfenadine, α-(4-tert-butylphenyl) -4-hydroxydiphenylmethyl)- 1-piperidinebutanol (16.1.24), is synthesized in two ways. According to the first, benzyl-4- magnesiumchloropiperidine is reacted with benzophenone, giving (1-benzyl-4-piperidyl) diphenylcarbinol (16.2.22), which undergoes further debenzylation by reduction with hydrogen using a palladium over carbon catalyst, giving (4-piperidyl)diphenylcarbinol (16.2.22). This product is alkylated by either 1-(4-tert-butylphenyl)-4-chlorobutanol, which forms terfenadine (16.1.24), or by alkylating with (4-tert-butylphenyl-3-chloropropiophenone, which forms the product (16.1.25), the carbonyl group of which is reduced to an alcohol group, thus giving the desired terfenadine (16.1.24).

InChI:InChI=1/C32H41NO2/c1-31(2,3)26-18-16-25(17-19-26)30(34)15-10-22-33-23-20-29(21-24-33)32(35,27-11-6-4-7-12-27)28-13-8-5-9-14-28/h4-9,11-14,16-19,29-30,34-35H,10,15,20-24H2,1-3H3/p+1/t30-/m1/s1

Upstream product

• 43076-30-8 4'-tert-butyl-4-[4-(α-hydroxy-α-phenylbenzyl)piperidino]butyrophenone 
• 43076-44-4 1-<4-(1,1-Dimethylethyl)phenyl>-4-<4-(hydroxydiphenylmethyl)-1-piperidinyl>-1-butanone Hydrochloride 
• 115-46-8 C₁₈H₂₁NO 
• 43076-61-5 4'-tert-butyl-4-chlorobutyrophenone 
• 863029-85-0 1-(4-(tert-butyl)phenyl)prop-2-en-1-ol 
• 201230-82-2 carbon monoxide 
• 1025942-33-9 O-trimethylsilyl Terfenadine 
• 71607-31-3 Di-p-toluoyl-L-tartaric acid monohydrate 

Downstream Products

• 43076-30-8 4'-tert-butyl-4-[4-(α-hydroxy-α-phenylbenzyl)piperidino]butyrophenone 
• 83799-24-0 fexofenadine 

Relevant articles and documents

METHODS AND COMPOSITIONS FOR TREATING INFECTION

Provided herein are compositions and methods for treating or preventing infection.

Repurposing the antihistamine terfenadine for antimicrobial activity against staphylococcus aureus

Staphylococcus aureus is a rapidly growing health threat in the U.S., with resistance to several commonly prescribed treatments. A high-throughput screen identified the antihistamine terfenadine to possess, previously unreported, antimicrobial activity against S. aureus and other Gram-positive bacteria. In an effort to repurpose this drug, structure-activity relationship studies yielded 84 terfenadine-based analogues with several modifications providing increased activity versus S. aureus and other bacterial pathogens, including Mycobacterium tuberculosis. Mechanism of action studies revealed these compounds to exert their antibacterial effects, at least in part, through inhibition of the bacterial type II topoisomerases. This scaffold suffers from hERG liabilities which were not remedied through this round of optimization; however, given the overall improvement in activity of the set, terfenadine-based analogues provide a novel structural class of antimicrobial compounds with potential for further characterization as part of the continuing process to meet the current need for new antibiotics.

Identification of terfenadine as an inhibitor of human CD81-receptor HCV-E2 interaction: Synthesis and structure optimization

Terfenadine (4-[4-(hydroxydiphenylmethyl)-1-piperidyl]-1-(4-tert- butylphenyl)-butan-1-ol) was identified in a biological screening to be a moderate inhibitor (27 % inhibition) of the CD81-LEL-HCV-E2 interaction. To increase the observed biological activity, 63 terfenadine derivates were synthesized via microwave assisted nucleophilic substitution. The prepared compounds were tested for their inhibitory potency by means of a fluorescence labeled antibody assay using HUH7.5 cells. Distinct structure-activity relationships could be derived. Optimization was successful, leading to 3g, identfied as the most potent compound (69 % inhibition). Experiments with viral particles revealed that there might be additional HCV infection reducing mechanisms.

HYDROAMINOMETHYLATION OF OLEFINS

The present invention relates to a method comprising the step of contacting under hydroaminomethylation conditions, an olefin, an amine, a rhodium-phosphorous ligand, and synthesis gas (syngas). In particular, it has been discovered that, under some circumstances, a neutral rhodium-monodentate phosphite ligand is prescribed. The invention provides a simple way of making, in high yields and regiospecificity, a variety of products, including pharmacologically active products such as ibutilide, terfenadine, and fexofenadine, and derivatives thereof.

Process and diastereomeric salts useful for the optical resolution of racemic a-[4- (1,1-dimethylethy) phenyl) -4- (hydroxydipenylmethyl) -1-piperidinebutanol and derivative compounds

A process and diastereomeric salts useful for the optical resolution of racemic alpha-[4-(1,1-dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1-piperidinebutanol, 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid and lower alkyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetates. The process comprises placing into solution a chiral resolving agent, either (+)/(-)-di-paratoluoyltartaric acid or (-)/(+)-mandelic acid, in an amount equimolar to a compound corresponding to the desired enantiomer of the above compound, precipitating the resulting diastereomeric salt between the chiral resolving agent and the target enantiomer and separating the enantiomer.

Method of preparing a polymorph of terfenadine

The invention relates to a method for preparing HMP terfenadine comprising the steps of reacting terfenadone free-base with sodium borohydride to yield mixed polymorph terfenadine and crystallizing said mixed polymorph terfenadine from a seeded ester or ketone solvent system to yield substantially pure HMP terfenadine.

Structure-activity relationships within a series of analogues of the histamine H1-antagonist terfenadine

A number of terfenadine derivatives including terfenadine enantiomers were synthesized and tested for histamine H1-receptor affinity. No significant differences in H1 activity were found between terfenadine enantiomers. Qualitative structure-activity relationship studies identified the α,α-diphenyl-4-piperidinomethanol moiety as the pharmacophore for the H1 activity of this group of compounds. The major role of the phenylbutanol moiety in terfenadine seems to be preventing the compound from crossing the blood-brain barrier.

Process for the preparation of the high melting polymorphic form of terfenadine

A process for the preparation of the high-melting polymorphic form of terfenadine which comprises dissolving terfenadine in acetone, diluting the solution with water and recovering the crystalized product.

Preparation of the low melting polymorphic form of terfenadine

A process for the preparation of the low-melting polymorphic form of terfenadine involving controlled heating and subsequent cooling of a solution of terfenadine in an appropriate solvent.

Process for preparing 1-(p-tert-butylphenyl)-4-[4'-(alpha-hydroxy-diphenylmethyl)-1'-piperidinyl]butanol

The present invention relates to a process for preparing terfenadine which is based on the reduction of terfenadone by an alkali metal borohydride, said process being characterized in that the reaction is carried out in a two-phase system in the presence of a phase transfer catalyst. The process of the present invention permits obtaining terfenadine in each of the two substantially pure polymorphic forms directly .