Duloxetine synthesis

The importance and versatility of the Friedel-Crafts reaction in thiophene chemistry can be seen in the following examples of duloxetine synthesis involving Friedel-Crafts acylations. Duloxetine (Cymbalta) is a serotonin-norepinephrine reuptake inhibitor (SNRI) known for its use as an antidepressant. 

As another successful application of Noyori s TsDPEN ligand, Yan et al. reported the synthesis of antidepressant duloxetine, in 2008. Thus, the key step of this synthesis was the asymmetric transfer hydrogenation of 3-(dime-thylamino)-l-(thiophen-2-yl)propan-l-one performed in the presence of (5,5)-TsDPEN Ru(II) complex and a HCO2H TEA mixture as the hydrogen donor. The reaction afforded the corresponding chiral alcohol in both high yield and enantioselectivity, which was further converted in two steps into expected (5)-duloxetine, as shown in Scheme 9.17. 

R)-liINAP-RuBr2 can be successfully applied to the enantioselective hydrogenation of /i-kelo esters in the synthesis of (+)-(2R,3 W)-corynomycolic acid 115. ( S )-MeO-BIPHEP-RuBr2 was used in a similar manner in the synthesis of (R)-fluoxetine (116, Prozac ) and (S)-duloxetine (117).648... 

The original synthesis of duloxetine (3) is relatively straightforward, involving a four-step sequence from readily available 2-acetylthiophene 30 (Scheme 14.7). Understandably, the main synthetic challenge stems from the presence of a chiral center, because duloxetine (3) is marketed as the (5)-enantiomer as shown. Thus, a Mannich reaction between 30 and dimethylamine generated ketone amine 31, which was then reduced to provide intermediate racemic alcohol amine 32. The desired optically active (5)-alcohol 32a was accessed via resolution of racemate 32 with (5)-(+)-mandelic acid, which provided the necessary substrate for etherihcation with 1-fluoronaphthalene to afford optically active amine 33. Finally, A -demethylation with 2,2,2-trichloroethyl chloroformate and cleavage of the intermediate carbamate with zinc powder and formic acid led to the desired target duloxetine (3). 

More recently a rhodium-catalyzed enantioselective synthesis of duloxetine (3) has been reported (Scheme 14.17). In this work, readily available amino ketone 51 was converted to (6)-aminoalcohol 36 in 75% yield and greater than 99% ee. The intermediate alcohol was subsequently converted into duloxetine (3) in a single step via standard etherification. 

The nature of the aromatic substituents is apparently not critical for SSRI activity, as indicated by the structure of duloxetine (23-5), where one ring is replaced by thiophene and the other by naphthalene. The synthesis starts as above by the formation of the Mannich base (23-1) from 1-acetyl thiophene with formaldehyde and dimethyl-amine. Treatment of that intermediate with the complex from lithium aluminum hydride and the 2R,3S entantiomer of dimethylamino-l,2-diphenyl-3-methyl-butane-2-ol gives the S isomer (23-2) in high enantiomeric excess. Treatment of the aUcoxide from (23-2) and sodium hydride with 1-fluoronaphthalene leads to the displacement of halogen and thus the formation of ether (23-2). The surplus methyl group is then removed by yet another variant of the von Braun reaction that avoids the use of a base for saponifying the intermediate urethane. Thus, reaction of (23-3) with trichloroethyl formate leads to the A -demethylated chlorinated urethane (23-4). Treatment of that intermediate with zinc leads to a loss of the carbamate and the formation of the free secondary amine duloxetine (23-5) [23]. 

Candida tropicalis PBR-2, a yeast strain isolated from soil, is capable of carrying out the enantioselective reduction of N,N-dimethyl-3-keto-3-(2-thienyl)-l-propanamine 58 to (S)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)-l-propanamine 59 (Fig. 18.18), a key intermediate in the synthesis of the chiral drug (S)-Duloxetine (Soni and Banerjee, 2005). The organism produced the enantiopure (S)-alcohol with a good yield (>80%) and almost absolute enan-tioselectivity, with an ee >99%. Parameters of the bioreduction reaction were optimized and the optimal temperature and pH for the reduction were found to be 30 °C and 7.0, respectively. The optimized substrate and the resting cell concentration were lg/1 and 250 g/1, respectively. The preparative-scale reaction using resting cells of C. tropicalis yielded the (S)-alcohol at 84-88% conversion and ee >99%. 

The Role of Water in the Stabilization of Less-soluble Diastereomeric Salts -A Key Intermediate for the Synthesis of Duloxetine, 3-(Methylamino)-l-(2-thienyl)propan-l-ol [1 7]... 

Duloxetine (LY-248686), (S)-(-i-)-N-methyl-3-(l-naphthyloxy)-3-(2-thienyl)propyl-amine, is expected to be not only a new potent antidepressant but also a NE (norepinephrine) reuptake inhibitor, a 5-HT (serotonin) reuptake inhibitor, and a new treatment drug for stress urinary incontinence [18]. In order to produce an enantiopure key intermediate for the synthesis of the (S)-amine, the Eli Lilly group proposed various strategies [19]. As a result, they selected the enantioseparation of racemic 3-(dimethylamino)-l-(2-thienyl)propan-l-ol with (S)-mandelic acid by diastereomeric salt formation as the most economic and suitable process for industrial-scale production with efficient supporting techniques such as the racemization of the antipode and recycling the recovered materials [20]. However, in the process of demethylation for the preparation of (S)-Duloxetine from (S)-3-(di-methylamino)-l-(2-fhienyl)propan-l-ol, there are some critical problems, such as low yield and considerable decomposition to give impurities. Thus, a direct synthesis of (S)-Duloxetine starting from (S)-3-(methylamino)-l-(2-thienyl)propan-l-ol is expected to be a new route for the production of (S)-Duloxetine. 

B. A. Astieford, L. O. Weigel, Chirality in Industry II Resolution Versus Stereoselective Synthesis in Drug Development Some Case Histories, Duloxetine (LY248686), A. N. Collins,... 

Polymer-supported chiral sulfonamides also proved to be efficient catalysts for the enantioselective reduction of P-keto-nitriles [54]. This was demonstrated in the synthesis of anti-depressant drugs -fluoxetine 43 and -duloxetine (Scheme 4.11). 

The following acylation reactions of thiophenes are regioselective (C2) and high yielding. Both reactions are key C-C bond forming reactions that have been used in the synthesis of duloxetine. ... 

Jurczak and co-workers have developed an enantioselective variation of the Friedel-Crafts reaction to produce hydroxyl(thiophene-2-yl)acetates from the reaction of thiophenes with glyoxylates in the presence of a chiral BINOL-titanium catalyst. The desired thiophenes can be produced in high enantiomeric excess and can be utilized as a key intermediates in the synthesis of duloxetine. 

A formal synthesis of duloxetine, shown below, was developed that involved an enantioselective allylation of thiophene-2-carbaldehyde (14ASC199). 

The possible amino ketone precursors (186b and 186h) for the synthesis of both (5)-fluoxetine and (5)-duloxetine, respectively, were subjected to gram-scale asymmetric hydrogenation with a high substrate-to-catalyst ratio (S/C = 6000). Both products were obtained in 75% yield with 98% and >99% ee, respectively. The y-amino alcohols obtained could be converted to these important antidepressants in a single step. 

High-throu put, multi-dimensional substrate-catalyst screening was described by Adolfsson et al. for the ATH of heteroaryl alkyl ketones. The evaluated mthenium and rhodium precatalysts were derived from a library of modular amino acid-based ligands. The results of screening were used as a key step in the formal synthesis of the antidepressant drugs, (/f)-Huoxetine and (5)-Duloxetine. The ATH... 

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. 

Asymmetric synthesis is also common. Another technique is kinetic resolution. Kinetic resolution relies upon a difference in reactivity between the two enantiomers. For example this technique can be used in the synthesis of duloxetine. Duloxetine is marketed as the hydrochloride salt under the tradename Cymbalta as an antidepressant. It is a selective serotonin and norepinephrine reuptake inhibitor. It is the S enantiomer which is used. 

Figure 13.9 Stereoselective synthesis of chiral precursor of duloxetine catalyzed by ketoreductase.

Lipase-catalyzed acetylation of 3-hydroxy-3-substituted pro-panenitriles for the global synthesis of fluoxetine, tomoxetine, nisoxetine, and duloxetine enantiomers. 

DIPE as solvent [168]. The access to both (R)- and (S)-enantiomers was elegantly developed by the enzyme-catalyzed KR. Similarly, the lipase-catalyzed acetylation of 3-hydroxy-3-(2-thienyl)propanenitrile using PSL and later chemical modifications led to the synthesis of duloxetine enantiomers, which are also antidepressant agents [169]. The DKR of the p-hydroxynitrile precursor of duloxetine reported by Backvall and coworkers has allowed the improvement of the overall yield for the synthesis of these drug enantiomers (Figure 9.17) [170]. 

Kamal, A., Khanna, G. B. R., Ramu, R., and Krishnaji, T. (2003). Chemoenzymatic synthesis of duloxetine and its enantiomer Lipase-catalyzed resolution of 3-hydroxy-3-(2-thie-nyl) propanenitrile. Tetrahedron Lett., 44,4783-4787. 

Analogously, aryl 2-chloro[l- C]ethyl carbinols 49 (Figure 11.19) are accessible by CBS- or IpCaBCl-mediated reduction of aryl (2-chloro)ethyl[carbonyl- C]ketones e.e.s are usually > 90%. Replacement of chlorine with iodine followed by treatment with a primary amine converted haloalcohol 49 (Ar = thien-2-yl) into the 3-aryl-3-hydroxy[3- C]propy-lamine derivative 52, which served as the penultimate intermediate in the preparation of the carbon- 14-labeled CNS-active drug duloxetine" . Furthermore, Mitsunobu reaction (DEAD or ADDP, PhsP or BU3P) on 49 (Ar = phenyl) in the presence of various phenols provided the respective (R)- j8-haloethers with inversion of the configuration at the stereogenic center. This route was followed for the synthesis of [ CJatomoxetine and one of its metabolites. ... 

Chiral amino alcohols are common structures in drug molecules for example, y-secondaiy aminoalcohols are key intermediates in the synthesis of several pharmaceuticals, examples of which are shown in Scheme 14.12. Zhang has shown that Rh-DuanPhos catalysts can be used to synthesise these key intermediates directly via asymmetric hydrogenation of the p-secondary amino ketone. Application to the synthesis of the antidepressant duloxetine is shown in Scheme 14.12. It should be noted that, to date, ruthenium catalysis has not been successfully applied to the reduction of secondary amino substrates a tertiary amino group is required resulting in a less efficient synthesis requiring extra S3mthetic steps. ... 

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