A Second Generation Synthesis of Benzyl Piperidine Derivatives: A Key Intermediate for the Preparation of SERT/5-HT_1A Dual Inhibitor

Abstract

A second generation process for benzyl piperidine 10 is described. By the use of a Horner−Wadsworth−Emmons reaction and selective hydrogenation with Pt/C in ethyl acetate, 2-bromo-5-(hydroxymethyl) phenol 14 was efficiently converted to the compound 10 on a 5 kg scale. A small amount of water was found to be critical to complete the selective hydrogenation with low levels of debrominated byproduct 15. Impurities of the compound 10 were controlled by limiting the quality of 2-bromo-5-(hydroxymethyl) phenol 14 and 1-bromo-2-methoxyethane 15. ■ INTRODUCTIONIncreasing numbers of patients are affected by neuropsychiatric disorders such as schizophrenia, bipolar disorder, and depression. Selective serotonin reuptake inhibitors (SSRIs) such as escitalopram and paroxetine are commonly used for the treatment of depressions. However, the slow onset of the action is an issue. It has been reported that the combination of SSRIs with 5-HT 1A antagonists can accelerate the onset action of SSRIs, 1 so we have started a program to explore such new drug candidates. We were therefore pleased to find that the novel benzyl piperidine compound connected to a chromone core (1, Scheme 1) was a promising candidate as it is both a dual serotonin transport inhibitor and a 5-HT 1A inhibitor. 2 In the early stages of the clinical development, the intermediate 2 was manufactured by the route shown in Scheme 2. Nucleophilic addition of 2-methoxyethanol to 4-bromo-3-fluorobenzoic acid 4 gave 5 in 87% yield. A diborane reduction of the carboxylic acid 5 gave the benzyl alcohol 6, which was sufficiently pure for the next step. Bromination with 47% aqueous HBr/toluene system, followed by treatment with triphenyl phosphine, precipitated the phosphonium salt 8 in 78% yield over 3 steps. A Wittig reaction of 8 with N-Boc piperidone in 2-propanol in the presence of K 2 CO 3 gave a clean conversion to 9, which was hydrogenated with Rh/C in ethyl acetate to give 10, together with the debrominated 18. Refluxing 10 in 2-propanol with concentrated hydrochloric acid removed the Boc group, and after recrystallization, the hydrochloride of 2 was obtained in 87% yield over three steps. The overall yield of the hydrochloride of 2 from 4-bromo-3-fluorobenzoic acid 4 was 58%.The route was successfully scaled up to supply 40 kg of API for early clinical trials. However, the route needed to be improved for future material supply due to the following three problems:i. In the first step, hydrogen fluoride is formed at acidic workup. ii. After the Wittig reaction, silica gel column chromatography was needed to remove phosphine oxide.iii. At the hydrogenation step, 40 wt % (vs starting material 9) of expensive 10% Rh/C (50% wet) was needed for full conversion. ■ RESULTS AND DISCUSSIONTo address these problems, new routes were investigated. A potential second generation synthesis was found as shown in Scheme 3. We were delighted to find that the selective decarbonylative Heck reaction 3 of the acid chloride 11 and the methylene piperidine 12 gave 13, which was then hy...