Synthesis of Sertraline

Sertraline is an inhibitor of the synaptosomal serotonin uptake, and has been developed by Pfizer as a single isomer. After early attempts that were based on a classical resolution procedure [68], a catalytic stereoselective entry to the enantiomerically pure drug was established [69]. 

In this process (Fig. 22), ketone 61 underwent reduction with an over-stoichiometric amount of borane in THF in the presence of 5 mol % of the proline-derived Corey s oxa-zaborolidine 62 to afford alcohol 63 in 100% yield and 92% e.e. SN2 displacement carried out on the alcohol mesylate with a higher-order cuprate gave adduct 64, that was transformed first into tetralone 65 by a triflic acid-promoted Friedel-Crafts-type reaction, and then into sertraline 66 (86% e.e.) by imine formation and borohydride reduction. 

It is worth mentioning that when B-chlorodiisopinocampheylborane was used as a stoichiometric chiral reducing agent to convert 61 into 63, the latter was obtained in a slightly lower e.e. (88%) than that observed in the catalytic reaction [69]. 

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The Rh2(DOSP)4 catalysts (6b) of Davies have proven to be remarkably effective for highly enantioselective cydopropanation reactions of aryl- and vinyl-diazoacetates [2]. The discovery that enantiocontrol could be enhanced when reactions were performed in pentane [35] added advantages that could be attributed to the solvent-directed orientation of chiral attachments of the ligand carboxylates [59]. In addition to the synthesis of (+)-sertraline (1) [6], the uses of this methodology have been extended to the construction of cyclopropane amino acids (Eq. 3) [35], the synthesis of tricyclic systems such as 22 (Eq. 4) [60], and, as an example of tandem cyclopropanation-Cope rearrangement, an efficient asymmetric synthesis of epi-tremulane 23 (Eq. 5) [61]. 

The combined C-H activation/Cope rearrangement generates a new C-H bond in a highly stereoselective manner and, therefore, has the potential to be a strategic reaction in synthesis. An example of this is the enantiose-lective synthesis of (+)-sertraline as shown in Scheme l.91 The C-H insertion step proceeded smoothly to form 17 with 99% ee. The conversion of 17 to (+)-sertraline could be readily achieved using conventional steps. 

Table 16 Hydroalumination of oxabenznorbornadienes using BINAP as a key step in the synthesis of Sertraline...

The intramolecular C-H insertion reaction of phenyldiazoacetates on cyclohexadiene, utilizing the catalyst Rh2(S-DOSP)4, leads to the asymmetric synthesis of diarylacetates (Scheme 8). Utilizing the phenyl di azoacetate 38 and cyclohexadiene, the C-H insertion product 39 was produced in 59% yield and 99% ee. Oxidative aromatization of 39 with DDQ followed by catalytic hydrogenation gave the diarylester 40 in 96% ee. Ester hydrolysis followed by intramolecular Friedel-Crafts gave the tetralone 31 (96% ee) and represents a formal synthesis of sertraline (5). Later studies utilized the catalyst on a pyridine functionalized highly cross-linked polystyrene resin. ... 

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

The reaction of vinyldiazoacetates at allylic C-H sites does not result in the predominant formation of the products of a simple C-H insertion [25]. Instead, combined C-H insertion/Cope rearrangement products are formed with very high enantioselectivity as illustrated by the example shown in Eq. (20) [25]. This process has been applied to a very short asymmetric synthesis of (+)-sertraline (38). 

It seemed reasonable to conclude that 153 was formed by C-H insertion followed by a Cope rearrangement, yet thermolysis of 153 in refluxing hexane showed that the equilibrium actually lay in the opposite direction 152 was cleanly formed. Thus the formation of 153 was more likely due to a concerted reaction, in which the initial C-H activation is interrupted by a rearrangement that resembles a Cope rearrangement. This transformation was ideally suited to a short formal synthesis of (+)-sertraline (157, Scheme 37). 

Figure 22. Stereoselective synthesis of sertraline. Reagents a, BH3-THF b, MsCl, TEA, CH2C12 c, Ph2CuCNLi2, Et20 d, TfOH, benzene e, MeNH2, TiCl4, toluene f, NaBH4, MeOH.

For an example taken from a synthesis of (+)-sertraline, see Chandrasekhar, S. Reddy, M.V. Tetrahedron, 2000, 56,... 

Taber, G. P. Pfisterer, D. M. Colberg, J. C. A New and Simplified Process for Preparing N-[4-(3,4-Dichlorophenyl)-3,4-dihydro-l(2H)-naphthalenyl-idene]methanamine and a Telescoped Process for the Synthesis of (IS-cis)-4-(3,4-Dichlorophenol)-1,2,3,4-tetrahydro-N-methyL 1 -naphthalenamine Mandelate Key Intermediates in the Synthesis of Sertraline Hydrochloride. Org. Proa Res. Dev. 2004, [Pg.431]

In synthesis, the fewer steps, and the more steps that can be carried out without change of solvent, the better. Reichardt andWelton (2011, p. 512) mention two major successes in reduction of solvent use by Pfizer an amazing 180-fold reduction in solvent use in the synthesis of Viagra from discovery to the final, optimized scheme (Dunn et al, 2004), and the three steps in different solvents with isolation of intermediates at each stage in the synthesis of sertraline done all in ethanol with isolation of the final product only (Taber et al, 2004). 

Scheme 7.8 Enantioselective synthesis of sertraline based on desynunetrization of oxabenzonorbomadiene 7 and Suzuki coupling to (R)-12...

While the first four examples, Scheme 7.11a, demonstrate the high enantioselec-tivity of the process, the last example. Scheme 7.11b, provides an example of diastereoselective transfer. These latter results prompted the concise formal total synthesis of sertraline according to Scheme 7.12 [37]. 

Scheme 7.12 Synthesis of sertraline, (1S,4S)-1 in the key step Tsuji-Trost reaction affords (R)-25...

Enantioselective synthesis of (+)-sertraline, (15,45)-TM 9.3, can be completed starting from either achiral building blocks, completing the key reaction in an enantioselective fashion, or starting from chiral raw materials, available from the chiral pool of nature, and completing the key reaction in a diastereoselective mode. 

Example 9.7 One enantioselective synthesis of -)-sertraline TM 9.3 starts firom the easily available oxabenzonorbomadiene 2. This mew-compound is desym-metrized by the catalytic action of chiral complex Ni(ll)-(5)-BlNAP and diisobutylaluminium hydride as the reducing agent (Scheme 9.11) [18, 19]. 

Example 9.8 This is an example of the creative use of a chiral building block from nature in the synthesis of (+)-sertraline (15,46 )-TM 9.3. Asymmetric synthesis starts from D-glyceraldehyde available by oxidative splitting of maimose or ascorbic acid [23]. Protected as acetal 17, this aldehyde is coupled to -alkene 19 with phosphonate 18, a reagent in the Homer-Wads worth-Emmons reaction (Scheme 9.13). 

The same authors have also investigated the DKR of bicyclic diols into their diacetates indueed by a combination of Candida antarctica lipase B (CALB) and the same ruthenium catalyst as above. As shown in Scheme 8.50, these ehiral diaeetates were produced in excellent yields and almost complete diastereo- and enantioselectivities. The utility of this methodology was demonstrated by its application to the total synthesis of sertraline. In addition, these eonditions were also applied to the DKR of a p-hydrojynitrile to provide the corresponding chiral acetate in 87% yield and enantioselectivity of 98% ee, as shown in Scheme 8.50. Again, this protocol was applied to the total synthesis of another biologically active product, such as (R)-duloxetine. 

In a recent application, the Shvo catalyst 1 was used to oxidize enantiomerically pure bicyclic diols (R,R)-3 to the hydroxyketones (/ )-4 in acetone [46]. The acetone acts as the hydrogen acceptor and, interestingly, under these conditions, it was possible to stop the reaction after oxidation of one of the hydroxyl groups to give the hydroxyketones 4 in 82-85% yield and 97-98% ee (5). The hydroxyketones obtained are useful starting materials for the synthesis of natural products and biologically active compounds, and (f )-4b was used for the synthesis of Sertraline [46]. 

The same group reported the formal synthesis of sertraline (19), an antidepressant, based on the DKR of diol [64]. In this synthesis, the DKR of dl/meso-diol 16 was carried out with CAL-B (Novozym 435) and 6 in the presence of isopropenyl acetate, followed by enzymatic alcoholysis, to obtain single enantiomeric diol (R,R)-16, which was then converted to the key intermediate (18) of sertraline via four steps (Scheme 5.41). 

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