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Fexofenadine

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Fexofenadine Basic information

Product Name:
Fexofenadine
Synonyms:
  • TERFENADINECARBOXYLATE
  • alpha-dimethyl-tyl)-alph
  • benzeneaceticacid,4-(1-hydroxy-4-(4-(hydroxydiphenylmethyl)-1-piperidinyl)bu
  • mdl16455
  • terfenadineacidmetabolite
  • 2-(4-(1-HYDROXY-4-[4-(HYDROXY-DIPHENYL-METHYL)-PIPERIDIN-1-YL]-BUTYL)-PHENYL)-2-METHYL-PROPIONIC ACID
  • Fexofenadinebase
  • FEXOFENADINE(SUBJECTTOPATENTFREE)
CAS:
83799-24-0
MF:
C32H39NO4
MW:
501.66
EINECS:
801-893-7
Product Categories:
  • API
  • Histamine receptor
  • Intermediates & Fine Chemicals
  • Aromatics
  • Heterocycles
  • Metabolites & Impurities
  • Active Pharmaceutical Ingredients
  • Metabolites
  • Pharmaceuticals
Mol File:
83799-24-0.mol
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Fexofenadine Chemical Properties

Melting point:
218-220°C
Boiling point:
697.3±55.0 °C(Predicted)
Density 
1.171±0.06 g/cm3(Predicted)
storage temp. 
Sealed in dry,Store in freezer, under -20°C
solubility 
Methanol (Slightly, Heated, Sonicated)
form 
Solid
pka
4.43±0.10(Predicted)
color 
White to Off-White
BCS Class
1,3
LogP
2.81
CAS DataBase Reference
83799-24-0(CAS DataBase Reference)
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Safety Information

Hazardous Substances Data
83799-24-0(Hazardous Substances Data)
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Fexofenadine Usage And Synthesis

Description

Fexofenadine, the carboxylic acid metabolite of terfenadine, is widely available. It accounts for the antihistaminic properties of terfenadine, which is very rapidly metabolized via CYP3A4-catalyzed processes. Members of the organic anion transporter protein family and the drug efflux transporter P-glycoprotein are involved in the disposition of fexofenadine. Fexofenadine does not have the antiarrhythmic side effects of terfenadine.

Chemical Properties

White Powder

Originator

Alernex,Dabur Pharmaceuticals Ltd.,India

Uses

A metabolite of of terfenadine, a H1-Histamine receptor antagonist

Uses

The active metabolite of Terfenadine (T114500), a H1-histamine receptor antagonist.

Definition

ChEBI: A piperidine-based anti-histamine compound.

Manufacturing Process

Microbiological Preparation of Fexofenadine (Patent U.S. 6,558,931)
Ten 250 ml Erlenmeyer flasks containing 100 ml of medium D are seeded with A. corymbifera LCP 63-1800. 50 mg of Terfenadine in 1 ml of ethanol is added to each Erlenmeyer flask. The content of 10 Erlenmeyer flasks are filtered on gauze (the supernatant has a pH equal to 8.0), and saturation with sodium chloride is carried out for 2 hours (pH = 5-6), followed by extracting 3 times with ethyl acetate and drying over magnesium sulfate. After evaporation under reduced pressure, 409 mg of expected crude product is obtained (yield = 77%, approximately 90% pure product). This product is purified on a column of silica gel (230-400 mesh, 40 g of silica, diameter = 3 cm) eluting with a methylene chloride/methanol/ammonium hydroxide mixture (82.5:15:2.5). 312 mg of pure Fexofenadine is recovered (61.4%).
Synthesis of Fexofenadine (Patent U.S. No. 5,578,610
Aluminum chloride (44 g; 0.33 mol) was added in portions to a solution of freshly distilled 4-chlorobutyryl chloride (17 mL; 0.15 mol) in 460 mL of carbon disulfide at -10°C under a nitrogen atmosphere. The mixture was stirred for 15 min, then the cooling bath was removed and the mixture was allowed to warm to ambient temperature. The mixture was stirred then for 15 min more, then cooled again to -10°C and a solution of ethyl-α,α- dimethylphenyl acetate (26.6 g; 0.14 mol) in 70 mL of carbon disulfide was added dropwise. The mixture was stirred for 3 hours, then stirred overnight at room temperature. The reaction mixture was partitioned between water and CHCl3. The combined organic portions were dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in CH2Cl2 and filtered through a plug of SiO2, eluting with 10% EtOAc in hexane. Yield of ethyl 3- and 4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetate 39.4 g (as a mixture of aromatic regioisomers).
To a solution of 39.4 g of ethyl 3- and 4-(4-chloro-1-oxobutyl)-α,α- dimethylphenylacetate dissolved in 800 mL of methanol and 200 mL of water was added 40 g of NaOH. The mixture was refluxed for one hour. The cooled mixture was then concentrated in vacuo. The concentrate was diluted with water and washed with 2 portions of EtOAc. The aqueous layer was acidified with concentrated HCl and extracted with 2 portions of EtOAc. The extracts were dried over MgSO4, filtered, and concentrated in vacuo to afford 30.3 g of crude product. The crude product was dissolved in 600 mL of EtOAc, 38 g of cinchonidine was added, and the mixture was stirred overnight. The resulting solids were filtered and washed with EtOAc and sucked dry under a rubber dam to afford 25 g of a solid 4-(cyclopropyl-oxo-methyl)-α,α- dimethylphenylacetic acid.
A solution of 10.5 g of 4-(cyclopropyl-oxo-methyl)-α,α-dimethylphenylacetic acid in 250 mL of CH2Cl2 was cooled in an ice-MeOH bath and 25 g of trimethylsilyliodide was then added via pipette. The mixture was stirred in the ice bath for one hour, warmed to ambient temperature, and stirred for one hour. A solution of aqueous sodium bisulfite was then added and the mixture was stirred well. The phases were partitioned and the aqueous layer was extracted with CH2Cl2. The combined organics were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated in vacuo to afford 12.6 g (77%) of 4-(4-iodo-1-oxobutyl)-α,α-dimethylphenylacetic acid.
To a solution of 12.6 g of 4-(4-iodo-1-oxobutyl)-α,α-dimethylphenylacetic acid in 100 mL of ether cooled in an ice bath, was added 40 mL of ethereal CH2N2. The mixture was stirred at 0°C for few minutes, then let stand for 2 hours. A few drops of AcOH were added to decompose excess CH2N2, then the mixture was filtered and stripped to afford 12.6 g (96%) of methyl 4-(4-iodo-1- oxobutyl)-α,α-dimethylphenylacetate.
A solution of 12.6 g of methyl 4-(4-iodo-1-oxobutyl)-α,α- dimethylphenylacetate in 500 mL of toluene in a one liter three neck flask was added 8.8 g of 4-(α,α-diphenyl)piperidinemethanol and 23 g of K2CO3 and the mixture was refluxed for 7 hours. The cooled reaction mixture was then filtered and concentrated in vacuo. The residue was dissolved in ether and treated with excess ethereal HCl. The mixture was then concentrated to a solid. The solid was treated with EtOAc and collected by filtration. The product was then partitioned between EtOAc and 2 N Na2CO3. The organics were dried over MgSO4, filtered, and concentrated in vacuo to afford 13.5 g (79%) of methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α- dimethylphenylacetate.
A solution of 13.5 g of methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]- 1-oxobutyl]-α,α-dimethylphenylacetate in 250 mL of methanol was cooled in an ice-methanol bath and 1.8 g of NaBH4 was added in portions. After 1 hour, the mixture was concentrated to a solid. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous portion was extracted with EtOAc. The combined organics were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated in vacuo to afford 9.5 g (70%) of methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1- hydroxybutyl]-α,α-dimethylphenylacetate as a foam.
To a solution of 9.5 g of methyl-4-[4-[4-(hydroxydiphenylmethyl)-1- piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetate in 300 mL of methanol and 150 mL of water was added 10 g of NaOH. The mixture was refluxed for 1 hour, then cooled. The methanol was removed in vacuo. The concentrate was diluted with water and CHCl3 and the pH adjusted to approximately 5.5 to 6.0. The phases were separated and the aqueous phase was extracted with CHCl3. The combined organics were dried over MgSO4, filtered, and stripped to afford 9.0 g of crude product. The crude product was dissolved in CH2Cl2 and chromatographed on Davisil Grade 633 SiO2 eluting with a gradient of CHCl3, to 10% of methanol in CHCl3, to 25% of methanol in CHCl3. The product was concentrated to afford 5.2 g of white crystals of 4-[4-[4- (hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetic acid (Fexofenadine).
In practice it is usually used as hydrochloride salt.

Therapeutic Function

Antihistaminic

FexofenadineSupplier

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