Fexofenadine Alcohol

Micro-organisms Culture medium Terfenadine Fexofenadine Alcohol... 

In 1996, a group from Sandoz (now part of Novartis) reported their synthesis of fexofenadine (3). Cbz protection of commercially available ethyl piperidine-4-carboxylate (34) was achieved using Af-(benzyloxycarbonyloxy)succinimide to afford 35. Treatment of 35 with three equivalents phenyl magnesium bromide led to tertiary alcohol... 

Vermeeren, A. and O Hanlon, J.F., Fexofenadine s affects, alone and with alcohol, on driving and psychomotor performance, J. AUerg. Clin. Immunol., 101, 306, 1998. 

In a randomized, double blind, six-way, crossover study of the cognitive effects of fexofenadine 180 mg, both alone and in combination with alcohol, fexofenadine had no disruptive effects on objective measures related to driving a car and aspects of psychomotor and cognitive function, even when combined with a dose of alcohol equivalent to 0.3 g/kg (62). 

Ridout F, Shamsi Z, Meadows R, Johnson S, Hindmarch I. A single-center, randomised, double-blind, placebo-con-trolled, crossover investigation of the effects of fexofenadine hydrochloride 180 mg alone and with alcohol, with hydroxyzine hydrochloride 50 mg as a positive internal control, on aspects of cognitive and psychomotor function related to driving a car. Clin Ther 2003 25 1518-38. 

SODIUM OXYBATE 1. ALCOHOL 2. ANALGESICS - opioids 3. ANTIDEPRESSANTS-TCAs 4. ANTIEPILEPTICS-barbiturates 5. ANTIHISTAMINES 6. ANTIPSYCHOTICS 7. ANXIOLYTICS AND HYPNOTICS-BZDs, buspirone Risk of CNS depression - coma, respiratory depression Additive depression of CNS Avoid co-administration. Caution even with relatively non-sedating antihistamines (cetrizine, desloratidine, fexofenadine, levocetirizine, loratidine, mizolastine) as they can impair the performance of skilled tasks... 

Weiler JM, Bloomfield JR, Woodworth GG, Grant AR, Layton TA, Brown TL, McKenzie DR, Baker TW, Watson GS. Effects of fexofenadine, diphenhydramine, and alcohol on driving performance. A randomized, placebo-controlled trial in the Iowa driving simulator. Ann Intern Med 2000 132(5) 354-63. 

The non-sedating antihistamines seem to cause little or no drowsiness in most patients and the risks if taken alone or with alcohol appear to be minimal or absent. However, the incidence of sedation varies with the non-sedating antihistamine (e.g. sedation appears to be lower with fexofenadine and loratadine than with acrivastine or cetirizine) and with the individual (e.g. women may be more affected than men). Therefore, patients should be advised to be alert to the possibility of drowsiness if they have not taken the drug before. Any drowsiness would be apparent after the first few doses. The patient information leaflets for acrivastine and cetirizine suggest avoidance of alcohol or excessive amounts of alcohol, and caution is advised with levocetirizine. ... 

Reductive amination of aldehydes prepared from hydrofonnylation is a useful route to amines. Botteghi, et al. reported the synthesis of racemic Tolterodine by sequential hydroformylation-reductive amination [18]. Hydroaminomethylation (tandem hydroformylation/reductive amination) has recently been used to prepare a wide variety of pharmaceutical compounds [19]. Representative examples are shown in Fig. 5. Hydroaminomethylation of 1,1-diarylethenes leads to l-(3, 3-diaiylpropyl)amines, such as fenpiprane [20, 21]. Heterocyclic aUyUc amines undergo hydroaminomethylation to form pharmaceutically active diamines, such as etymemazine [22]. Ibutilide and fexofenadine have been prepared by hydroamino-methylatiOTi of 1-aiylallyl alcohols in the presence of the requisite amines [23,24]. Although none of these reactirais has been developed into a commercial process, the widespread utility of the hydroaminomethylation reaction makes it likely that it will be used commercially... 

Fig. 4.16 Hydroxylalion of a methyl carbon in teifenadine. Two subsequent P450-catalyzed oxidations convert the alcohol metabolite to the acid that is present in fexofenadine...

HAM of substituted allyl alcohols results in biologically active tertiary amines, such as ibutilide and aripiprazole (Scheme 5.118) [57]. Protection of the allylic hydroxyl group was found to be unnecessary no lactol formation was observed during the hydroformylation step. The antihistamines terfenadine and fexofenadine were prepared in the same manner [102]. 

Fexofenadine, as the carboxylic analogue of terfenadine, is an amino acid with a highly hydrophilic zwitterionic stmcture. Its enantiomers have been separated repeatedly by chromatographic methods [9, 17, 18], and the CD spectra reveal a positive extreme for the f -(+)-enantiomer at 205 nm with a shoulder at 225 nm. The absolute configuration of the fexofenadine enantiomers was determined by chemical correlation with the alcohol S-(-)-12, for which the prediction of absolute configuration is based on the configuration of the chiral catalysts used in reduction. Details are presented in Scheme 10.9. 

It was found that the fungus, C. blakesleeana, was not able to perform the complete oxidation of terfenadine to fexofenadine, because the reactimi stopped at the level of the prim-alcohol. Since the prim-alcohol cannot be selectively oxidized with strong agents, such as RuCls or HslOe, but rather this occurs with the secondary hydroxy group, the result was disappointing for the scale-up process. 

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