Initial Process Development and Scale-Up of the Synthesis of a Triple Reuptake Inhibitor ALB 109780 Qiang Yang,* ,† Luckner G. Ulysse, † Mark D. McLaws, † Daniel K. Keefe, † Brian P. Haney, † Congxiang Zha, ‡ Peter R. Guzzo, ‡ and Shuang Liu ‡ † Chemical Development Department, AMRI, 21 Corporate Circle, Albany, New York 12203, United States ‡ Discovery R&D, AMRI, 30 Corporate Circle, Albany, New York 12203, United States ABSTRACT: Early process development toward a triple reuptake inhibitor is described. Three different routes were evaluated; one of them was optimized and scaled up to generate 470 g of API as this route minimized the formation of undesired side products. The selected route featured Eaton’s reagent-mediated cyclization of a phenyl acetamide, copper-mediated Buchwald- Hartwig coupling to install a morpholine moiety, and palladium-catalyzed α-arylation of a dihydroisoquinolinone to construct the core structure. ■ INTRODUCTION Major depressive disorder (MDD) is the leading cause of dis- ability in the U.S. for population ages 15-44. 1 It affects appro- ximately 14.8 million American adults, or about 6.7% of the U.S. population age 18 and older in a given year 2 and repre- sents a huge economic burden on society. 3 Despite the tremen- dous benefits of serotonin or dual serotonin and norepinephr- ine reuptake inhibitors (SSRIs and SNRIs, respectively) in treating depression, 30-40% of patients do not adequately respond to treatment with currently available antidepressants. 4,5 In pursuit of novel antidepressant therapies, our Discovery Research and Development colleagues identified ALB 109780 (1) (Figure 1) as a triple reuptake inhibitor (TRI, inhibits the reuptake of serotonin, norephinephrine, and dopamine) that could lead to improved treatment for depression. 6 In order to supply material for toxicological studies we were required to manufacture approximately 500 g of the active pharmaceutical ingredient (API). Herein we report the results of our initial development efforts and scale-up of the synthesis of ALB 109780. ■ RESULTS AND DISCUSSION Evaluation of the Synthesis of 9 via the Original Procedure. The original synthesis of the key intermediate 9 for the synthesis of 1 is depicted in Scheme 1. 7 Acyl chloride formation was originally conducted in 5 equiv of neat thionyl chloride with concentration to dryness and dissolution of the crude product in dichloromethane (DCM), followed by reac- tion with aqueous methylamine in tetrahydrofuran (THF). The reaction was quenched with water upon completion and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated to dryness to afford the desired amide in >95% HPLC purity. After optimization, compound 2 was suspended in two volumes of toluene and 10 mol % of DMF and treated under dose-controlled condition with 1.2 equiv of thionyl chloride at 40 °C to ensure complete reaction. The resulting solution was cooled to ambient temperature and transferred to an aqueous solution of methylamine at 0-25 °C. The resulting suspension was filtered to afford the desired amide 3 in 88-94% yields and excellent HPLC purity (96.4 to >99%). 8,9 Initially, the synthesis of 4 was conducted in polyphosphoric acid (PPA) at 160 °C with paraformaldehyde. Upon com- pletion, the reaction was quenched with water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated to dryness to afford an oil. In an effort to identify more process friendly conditions for this transformation, we found that at 80 °C Eaton’s reagent (P 2 O 5 in methanesulfonic acid) worked similarly to PPA. The desired cyclized product 4 was obtained in excellent yield by neutralization of the reaction to pH 8.0 with sodium hydroxide, followed by extraction of the product with isopropyl acetate (IPAc) and isolation by filtration after the organic layer was concentrated to a thick suspension. Multiple batches of the chemistry from 2 were successfully executed in our kilo laboratories on 2-3-kg scale and afforded the desired product in >90% yield and >92% HPLC purity. 8,9 With a steady supply of 4 in hand, our focus shifted to the evaluation of the downstream chemistry. However, difficulties were quickly encountered during preliminary development inves- tigations. A des-bromo impurity (6a, Figure 2) was observed in Received: January 6, 2012 Published: February 13, 2012 Figure 1. Structure of ALB 109780. Article pubs.acs.org/OPRD © 2012 American Chemical Society 499 dx.doi.org/10.1021/op3000064 | Org. Process Res. Dev. 2012, 16, 499-506