Paroxetine, synthesis

The enantiomerically pure 3-arylglutaric ester are precursors for the synthesis of (—)-paroxetine [10], a selective serotonin reuptake inhibitor used in the treatment of depression, obsessive compulsive disorder, and panic, and (i )-Baclofen [11], a GABAb receptor agonist, which is used cHnically in the treatment of spasticity (Chart 5.1). 

The chiral reduction of -substituted a,/3-unsaturated lactams with PMHS in the presence of (S)-/ -Tol-BINAP as the chiral ligand with a copper catalyst results in -substituted lactams in excellent yield and with greater than 90% ee.599 This method has been applied in an efficient enantioselective synthesis of the antidepressant (-)-paroxetine (Eq. 356). 

Paroxetine hydrochloride is a selective serotonin reuptake inhibitor that is used as an antidepressant. The chemoenzymatic synthesis can be carried out... 

It is remarkable that better enantioselectivities are achieved when CALB-catalyzed acylations of the alcohol are carried out in organic solvent rather than in water. Excellent enantioselectivities are obtained when the process is carried out with vinyl esters [22]. However, in some cases the use of vinyl or alkyl esters as acyl donors has the drawback of the separation of the ester (product) and the alcohol (substrate). A practical strategy to avoid this problem is the use of cyclic anhydrides [23]. In this case an acid is obtained as product, which can be readily separated from the unreacted alcohol by a simple aqueous base-organic solvent liquid-liquid extraction. This methodology has been successfully used for the synthesis of (-)-paroxetine as indicated in Scheme 10.11 [24]. 

Scheme 14- Synthesis of (-)-paroxetine using an asymmetric desymmetrization of a glutanc ester via enzymatic hydrolysis.

Several other methods have been utilized to produce the aminoalcohol 81. A ring expansion of prolinol 84 (derived from pyroglutamic acid (83) in eight steps) gave the trisubstituted chloropipendine 85. Dechlorination of 85 was accomplished under reductive radical conditions to give the aminoester 86, which was reduced to the aminoalcohol 81, thus completing the formal synthesis of (-)-paroxetine (6) (Scheme 15)." ... 

Synthesis of fluoxetine hydrochloride 10.3 Synthesis of sertraline hydrochloride 10.4 Synthesis of paroxetine hydrochloride 10.5 References... 

Beak used this method in a synthesis of (-)-paroxetine 97 (Paxil or Seroxat), a selective serotonin reuptake inhibitor.9 Lithiation of 92 with n-BuLi-(-)-sparteine and addition of the product 93 to the nitroalkene 94 yields the protected Z-enamine 95, as usual for reactions of lithiated allylamides, in >94% ee. Hydrolysis and reduction of the product, followed by mesylation and cyclisation gave the fnms-substituted piperidine 96. Displacement of the hydroxyl group by sesamol yielded (-)-paroxetine 97. 

The analogous reaction of unsaturated lactones and lactams is strongly accelerated in the presence of alcohols which protonate the copper enolate formed in the conjugate reduction.281 This protocol was used in an enantioselective synthesis of the antidepressant (—)-paroxetine 324. Here, the key step was the conjugate reduction of the lactam 322 by PMHS in the presence of /-amylalcohol and catalytic amounts of CuCl2, ( S)- -tol-BINAP, and sodium /-butoxide, giving the product 323 with 90% yield and 90% ee (Scheme 90).281 The second chirality center was installed by diastereoselective alkylation of 323. 

The use of chiral lithium amides in the preparation of biologically potent piperidines from highly enriched glutarimides is illustrated in the synthesis of the antidepressant drug substance (—)-paroxetine (Figure 7)107. 

A three-step synthesis of a precursor of paroxetine is described. An aza double Michael reaction was used to form the piperidine ring <03TL7429>. 

Paroxetine is an antidepressant marketed by GlaxoSmithKline as Paxil. Example 2 of U.S. 4,007,196 (to A/S Eerrosan) describes preparation on the free base from of paroxetine, while U.S. 4,721,723 (to Beecham Group Pic.) describes the synthesis of the crystalline hydrochloride hemihydrate, which is the preferred form to administer the drug. What is the cost of production of the API in the crystalline hydrochloride hemihydrate form ... 

Another example by Gotor and coworkers is kinetic resolution by acylation of a primary alcohol [52]. With cyclic anhydrides as acyl donors the reaction product (now bearing a carboxylic acid) could easily be separated from the mixture by alkaline extraction. The non-reacting enantiomer is an intermediate in the synthesis of (-)-paroxetine, a selective inhibitor of 5-hydroxytryptamine reuptake (Scheme 13.4). 

Linchpin dialkylation of primary amines continues to be a useful concept in the synthesis of piperidines. Such a ring closure was used in the synthesis of paroxetine intermediate 144 <04TL8065> (Scheme 57),... 

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