Venlafaxine preparation

Like bupropion, venlafaxine comes in immediate-release and extended-release preparations. The immediate-release form is taken twice a day starting at 37.5 to 75 mg/day and increased to 75 mg/day after 1 week. The effective dose range is 75-375mg/day. The extended release form is started once daily at 37.5mg/day and is also effective at 75-375 mg/day. The effective dose range is similar to the immediate-release form. 

Venlafaxine is a serotonin and noradrenaline reuptake inhibitor (SNRI). It shares these properties with the TCAs amitriptyhne, clomipramine and imip-ramine, but it is the first selective SNRI, with low affinity for muscarinic, histaminic and a-adrenergic receptors. At low doses serotonergic effects predominate, but at higher doses the reuptake of noradrenaline is significantly blocked (Melichar et al. 2001). It is available as immediate and extended release (XR) preparations. 

MAOIs have the most serious pharmacodynamic interactions of any antidepressant class. As discussed earlier, they can cause a hypertensive crisis and the serotonin syndrome. They potentiate the hypertensive effects of most sympathomimetic amines, as well as tyramine, which is the reason for the avoidance of over-the-counter preparations containing such agents, in addition to the tyramine-free diet ( 508, 509). The serotonin syndrome occurs most often when MAOIs are used in combination with SSRIs and venlafaxine but it can also occur when MAOIs are used with tryptophan, 5-hydroxytryptophan, and some narcotic analgesics. In addition, MAOIs can also significantly potentiate the sedative and respiratory depressant effects of narcotic analgesics. 

Venlafaxine 10 is a serotonin-noradrenaline reuptake inhibitor used in the treatment of depression. Several sila analogues of venlafaxine have been prepared the silacyclohexylderivative 11 (04WOP200494436), its desmethoxy derivative 12 (06JOM(691)3589) and silacyclopentyl... 

Summary Novel potential o ligands of the l,4 -silaspiro[tetralin-l,4 -piperidine] type (compounds lb - 4b, isolated as hydrochlorides) and rac-sila-venlafiixine (rac-5b, a silicon analog of the serotonin/noradrenaline leuptake inhibitor roc-venla xine (rac-5a)) were synthesized. In addition, the sila-venlafaxine enantiomers (i )-5b and (S)-5b and the sila-venla xine derivatives / ac-6-HCl and rac-T-HCl were prepared. Compounds 3b-HCl and rac-Sb-HCl were structurally characterized by single-crystal X-ray diffraction, and rac-Sa, rac-Sh, rac-6, and rac-7 were pharmacologically characterized. 

We report here on (1) the synthesis of the silicon-based potential a ligands lb - 4b (isolated as the hydrochlorides), (ii) the synthesis of rac-sila-venlafaxine (rac-Sb), (iii) the preparation of the slla-venlafaxine enantiomers (if)-5b and (S)-5b via resolution of rac-Sh, (iv) the synthesis of the sila-venlafaxine derivatives rac-6 and rac-7, (v) the crystal structure analyses of 3b-HCl and rac-5b HCl, and (vi) the pharmacological characterization of rac-5a, rac-5b, rac-6, and rac-7. Preliminary results of the studies reported here have already been presented elsewhere [6, 7]. 

R)-Sila-venlafaxine ((R)-5b) was prepared according to Scheme 3 by resolution of rac-5b, using (+)-10-camphorsulfonic acid ((+)-CSA) as the resolving agent (-> (R)-5b (+)-CSA). Treatment of the diastereomerically pure salt (R)-5b (+)-CSA (obtained by 3-fold recrystallization from acetone)... 

Scheme 3. Preparation of (/J)-sila-venlafaxine ((/f)-5b), (/i)-sila-venlafaxine hydrochloride ((/t)-5b-HCl), and (/ )-sila-venlafexine hydrobromide ((/ )-5b-HBr).

At the other extreme, trazodone, nefazodone, and venlafaxine have short half-lives (about 3 to 6 hours), as does the active 4-hydroxy metabolite of venlafaxine (half-hfe of about 11 hours). The half-life of bupropion is about 14 hours. Owing to rapid aromatic hydroxylation, the half-hfe of nefazodone is very short (about 3 hours). The shorter durahon of action of these agents usually imphes the need for mulhple daily doses. Some short-achng antidepressants have been prepared in slow-release preparations (notably bupropion and venlafaxine), to ahow less frequent dosing and potentiahy to temper side effect related to agitation and GI disturbance. 

Problem 20.27 What Grignard reagent and carbonyl compound can be used to prepare the antidepressant venlafaxine (trade name Effexor) ... 

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