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Fexofenadine hydrochloride

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Fexofenadine hydrochloride Basic information
Fexofenadine hydrochloride Chemical Properties
  • Melting point:148-150oC
  • RTECS CY1633377
  • storage temp. −20°C
  • solubility Soluble in Dimethyl sulfoxide (50 mM), and methanol.
  • form powder
  • color white to beige
  • Merck 14,4068
  • CAS DataBase Reference153439-40-8(CAS DataBase Reference)
Safety Information
  • Hazard Codes Xi
  • Risk Statements 36/37/38
  • Safety Statements 26-36
  • WGK Germany 3
  • HS Code 2933399090
Fexofenadine hydrochloride Usage And Synthesis
  • DescriptionFexofenadine hydrochloride (trade name: Allegra) belongs to a second-generation antihistamine pharmaceutical drug. It is mainly used for the treatment of allergy symptoms including watery eyes, hay fever, nasal congestion, urticaria, runny nose, itching eyes/nose, sneezing, hives, and itching. It is a kind of selectively peripheral H1 blocker. Its mechanism of action in vivo is through preventing the histamine-mediated activation of the H1 receptors, thus alleviating the symptoms related to allergy. Compared to the first-generation antihistamine drug, it is less prone to penetrate the blood-brain barrier, reducing the possibility to cause side effects such as drowsiness.
  • References
  • Chemical PropertiesOff-White Crystalline Solid
  • OriginatorAlernex,Dabur Pharmaceuticals Ltd.,India
  • UsesA metabolite of of terfenadine, a H1-Histamine receptor antagonist
  • UsesThe active metabolite of Terfenadine (T114500), a H1-histamine receptor antagonist.
  • UsesAntihistaminic;histamine H1-receptor antagonist
  • UsesFexofenadine is a non-sedating antihistamine that selectively antagonizes the histamine H1 receptor with a Ki value of 10 nM and exhibits anti-inflammatory effects. It is devoid of central nervous system effects in part because it is a good substrate for the P-glycoprotein efflux pump situated within the blood-brain barrier.[Cayman Chemical]
  • Manufacturing ProcessMicrobiological 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 FunctionAntihistaminic
  • General DescriptionFexofenadine hydrochloride, (±)-4-[1-hydroxy-4-[4-(hydroxyldiphenylmethyl)- 1-piperinyl]butyl-α,α-dimethylbenzeneacetic acid (Allegra), occurs as a white to off-white crystalline powder that is freely soluble in methanol and ethanol, slightly soluble in chloroform and water, and insoluble in hexane.
    This compound is marketed as a racemate and exists as a zwitterion in aqueous media at physiological pH. Fexofenadine is a primary oxidative metabolite of terfenadine. Terfenadine was developed during a search for new butyrophenone antipsychotic drugs as evidenced by the presence of the N-phenylbutanol substituent. It also contains a diphenylmethyl-piperidine moiety analogous to that found in the piperazine antihistamines.
  • Biological ActivitySelective histamine H 1 receptor antagonist (pK i = 8.1). Active metabolite of terfenadine that displays non-sedating antiallergic effects.牋.
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