Duloxetine Alcohol

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. 

Hepatotoxicity- Duloxetine increases the risk of elevation of serum transaminase levels. The combination of transaminase elevations and elevated bilirubin, without evidence of obstruction, is generally recognized as an important predictor of severe liver injury. Because it is possible that duloxetine and alcohol may interact to cause liver injury, duloxetine should ordinarily not be prescribed to patients with substantial alcohol use. 

Drugs that may affect duloxetine include inhibitors of CYP1A2 (eg, fluvoxamine, guinolone antibiotics), inhibitors of CYP2D6 (eg, fluoxetine, guinidine, paroxetine), and alcohol. 

Drugs that may be affected by duloxetine include drugs extensively metabolized by CYP2D6 (eg, flecainide, phenothiazines, propafenone, tricyclic antidepressants, thioridazine), alcohol, CNS-acting drugs, MAOIs, and drugs highly bound to plasma proteins (eg, warfarin). 

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). 

Subsequent synthetic literature around duloxetine (3) is focused around the description of stereoselective approaches to the critical alcohol intermediate 36, or similar derivatives. 

The first report in this regard described a method for direct formation of the desired optically active (S)-alcohol 32a, via enantioselective reduction with a chiral amine complex of lithium aluminum hydride (Scheme 14.9). Therefore, the necessary chiral hydride complex 38 was preformed in toluene at low temperature from chiral amino alcohol 37. The resulting hydride solution was then immediately combined with ketone 31 to afford the desired (S)-alcohol 32a in excellent yield and enantiomeric excess. In addition to providing a more efficient route to the desired drug molecule, this work also led to the establishment of the absolute configuration of duloxetine (3) as S). 

Kinetic resolution technology has also been applied to the duloxetine problem (Scheme 14.13). In this case, chloroketone 41 was converted to racemic alcohol 43 using sodium borohydride. The racemate was then treated with vinyl butanoate in hexanes, in the presence of catalytic immobilized Candida antarctica Lipase B (CALB). The reaction was stopped after reaching 50% conversion, leading to the isolation of the desired (5)-chloroalcohoI 43a, as well as the (Zf)-ester 45 in good yields and excellent enantiomeric excesses. Chloroalcohol 43a was converted to duloxetine (3) via the... 

Similarly, lipase-catalyzed kinetic resolution has also been applied to intermediate nitrile alcohol 46 (Scheme 14.14). Best results were obtained by using immobilized Pseudomonas cepacia (PS-D) in diisopropyl ether, leading to excellent yield and enantiomeric excess of the desired (5)-alcohol 46a, along with (/J)-nitrile ester 47. Reduction of 46a with borane-dimethylsulhde complex, followed by conversion to the corresponding carbamate and subsequent lithium aluminum hydride reduction gave rise to the desired (S)-aminoalcohol intermediate 36, a known precursor of duloxetine (3). 

Enantioselective catalytic hydrogenation has also been apphed to the preparation of optically active duloxetine intermediates (Scheme 14.15). In one such report, (3-keto amine 31 was converted to amino alcohol 32a in excellent enantiomeric excess without... 

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. 

Hepatotoxicity. Duloxetine is rarely associated with increases in serum transaminase levels, typically in the first 2 months of treatment. In controlled trials in major depressive disorder, elevations of alanine aminotransferase (ALT) to greater than three times the upper limit of normal occurred in 0.9% (8 of 930) of the duloxetine-treated patients and in 0.3% (2 of 652) of the placebo-treated patients. Current product labeling contains a caution regarding the use of duloxetine in patients with significant alcohol use or chronic liver disease. Postmarketing reports have indicated that increases in transaminases have occurred in some patients with chronic liver disease (Cymbalta 2005). 

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%. 

No important psychomotor interaction normally appears to occur between duloxetine or venlafaxine and alcohol. However, the manufacturer warns that use of duloxetine with heavy alcohol intake may be associated with severe liver injury. 

In a single-dose study in healthy subjects, duloxetine 60 mg, and alcohol given in a dose sufficient to produce blood levels of about 100 mg%, did not worsen the psychomotor impairment observed with alcohol alone. Nevertheless, the UK manufacturer advises caution, and the US manufacturer warns that duloxetine should ordinarily not be prescribed for patients with substantial alcohol use as severe liver injury may result. ... 

Skinner MH, Weerakkody G. Duloxetine does not exacerbate the effects of alcohol on psycho-mettic tests. Clin Pharmacol Ther (2002) 71,53. 

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. 

The precursor alcohol is formed as a racemate and then reacted with vinyl butanoate to 50% conversion in the presence of catalytic Canidida antarc-tica Lipase B (CALB). The undesired R alcohol esterifies faster. After 50% conversion, it has formed the ester and the desired S alcohol remains [43] for subsequent conversion to duloxetine. 

Corynomycollc acid isolated from the cell walls of Cor-ynebacterium sp. or related organisms exhibit immunostimu-lant properties.Duloxetine is a serotonin-norepinephrine reuptake inhibitor used in major depressive disorder, general anxiety disorder, stress urinary incontinence,diabetic peripheral neuropathy, fibromyalgia,and chronic musculoskeletal pain associated with osteoarthritis and chronic lower back pain. Fluoxetine is a serotonin-uptake inhibitor used as an antidepressant and for treatment of anxiety, alcoholism, and bulimia. " ... 

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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