Sertraline synthesis

Changing catalyst support from carbon to calcium carbonate leads to dramatic improvement of the cis/tran ratio from 6 1 to 18 1, that is the cis selectivity increases from 85.7% to 94.7%. The reason for better selectivity on CaC03 supported catalyst is attributed to its lower surface area leading to lower hydrogenation activity, but more selective to the desired product. The successful commercialization of the new route for sertraline synthesis demonstrates that for a stereoselective hydrogenation reaction, improve product selectivity can be achieved by proper selection of catalyst support. 

Compromise solvents are ideal when they can be identified, but, unfortunately, in many cases there will be no solvent that allows two consecutive steps to operate with acceptable performance. In the case of the sertraline synthesis, the last three steps required a total of four solvents (Figure 5). A compromise solvent, ethanol, was found by Pfizer to meet the needs of the last three steps, resulting in a 76% reduction in solvent volume. ... 

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 asymmetric reductive ring opening of oxabenzonorbomene 53 was applied as a key step in the total synthesis of serotonin re-uptake inhibitor sertraline [77, 80]. 

Approved for use in the U.S. in the early 1990s, Sertraline (Zoloft ) is the most prescribed drug of its class. In the original synthesis, the carbonyl group of the... 

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 vinylcyclopropane 10 is a useful chiral building block for organic synthesis, as the vinyl group can be oxidatively cleaved if desired and further functionahzed (Scheme 14.1). Either diastereomer 20 or 21 of the cyclopropane analog of phenylalanine can be readily prepared from 10 [40]. Corey has reported another elegant appHcation of the vinylcyclopropane 10 in the asymmetric synthesis of the antidepressant (-i-)-sertraline 22 [52]. 

The reaction of vinylcarbenoids with allylic C-H bonds leads to a remarkable transformation, a combined C-H insertion/Cope rearrangement, which is reminiscent of the tandem cyclopropanation/Cope rearrangement of vinylcarbenoids. An interesting application of this chemistry is the asymmetric synthesis of the antidepressant (-i-)-ser-traline 191 (Scheme 14.26) [134]. The Rh2(S-DOSP)4-catalyzed reaction of the vinyldia-zoacetate 189 with 1,3-cyclohexadiene generates the 1,4-cyclohexadiene 190 in 99% enantiomeric excess. The further conversion of 190 to (-t)-sertraline 191 is then achieved using conventional synthetic transformations. 

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). 

Sertraline [60], chiral 1,4-cycloheptadienes [61], and select cyclopentenes [62] have been prepared by using these catalysts and vinyldiazocarboxylates, and this approach has also been applied to the enantioselective synthesis of functionalized tropanes [63] and of the four stereoisomers of 2-phenylcyclopropane-l-amino acid [64]. 

Attempted allylic C-H insertion by vinyldiazoacetates results in an even more complicated transformation, a combined C-H activation/Cope rearrangement [27]. These reactions tend to proceed with very high enantioselectivity as illustrated in a short enantioselective synthesis of the antidepressant (+)-sertraline (33) [27a]. Recent studies have shown that this reaction is both highly diastereose-lective and enantioselective [27b],... 

Equally successful has been the group of Quallich at Pfizer46 who reported the preparation of a substituted dihydronaphthalenone, a pivotal intermediate in the preparation of the antidepressant sertraline (Lustral ) (10) (Scheme 16.6). In this synthesis, the new chiral center created subsequently determines the absolute stereochemistry of the final product (see Chapter 31). 

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