A Second Generation Synthesis of Benzyl Piperidine Derivatives: A

Aug 12, 2015 - ABSTRACT: A second generation process for benzyl piperidine 10 is ... bromo-5-(hydroxymethyl) phenol 14 and 1-bromo-2-methoxyethane 15...
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A Second Generation Synthesis of Benzyl Piperidine Derivatives: A Key Intermediate for the Preparation of SERT/5-HT1A Dual Inhibitor Atsushi Ueno, Nobuyuki Ae, Hideo Terauchi, Koji Fujimoto, and Yuji Fujiwara* Process Chemistry Research and Development Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan S Supporting Information *

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 2bromo-5-(hydroxymethyl) phenol 14 and 1-bromo-2-methoxyethane 15.

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INTRODUCTION Increasing 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-HT1A 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-HT1A 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 4bromo-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 K2CO3 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-3fluorobenzoic 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. © XXXX American Chemical Society

iii. At the hydrogenation step, 40 wt % (vs starting material 9) of expensive 10% Rh/C (50% wet) was needed for full conversion.

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RESULTS AND DISCUSSION To 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 reaction3 of the acid chloride 11 and the methylene piperidine 12 gave 13, which was then hydrogenated with Pt/C in toluene to give 10. The overall yield from commercially available 4 was 24% in 4 steps. Although this route was shorter than the first generation procedure, the yield from the coupling reaction was moderate (∼50%). The purity of 10 was also not satisfactory, and so a second recrystallization at the final step was necessary to improve its purity. Although we felt that this approach is attractive, due to the issues described, we decided to move to another process for further scale-up. The synthetic route we then established for the second generation synthesis of compound 10 is shown in Scheme 4.4,5 Alkylation of 2-bromo-5-(hydroxymethyl)phenol 14 with 15 proceeded efficiently in N-methyl pyrrolidone with powdered potassium carbonate as a base. When 1-chloro-2-methoxyethane was used instead of the bromide, the reaction did not complete. With KI as an additive, the reaction was faster but impurities increased, leading to a diminished yield and quality. After extraction, 6 was obtained as a toluene solution which was directly treated with 48% aqueous HBr at 70 °C for 2 h to give the benzyl bromide 7. Although compound 7 is a highly crystalline material, we were aware that this is strong irritant to eyes and skin even in a laboratory-scale experiment. So we decided to use it as a toluene solution in the next step without further purification. An Arbuzov reaction of the benzyl bromide 7 with triisopropyl phosphite gave the corresponding phosphonate 16. As neat conditions gave increased impurities, Received: June 25, 2015

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DOI: 10.1021/acs.oprd.5b00207 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Scheme 1. Process To Prepare 1

Scheme 2. Synthetic Route of Hydrochloride of 2 for Early Stage Development

Scheme 3. Route to 10 via Decarbonylative Heck Reaction

Scheme 4. Second Generation Synthesis of Compound 10

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DOI: 10.1021/acs.oprd.5b00207 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Table 1. Condition Optimization for the Horner−Wadsworth−Emmons Reactiona

a

entry

reagent

solvent

1 2 3 4 5 6 7 8 9 10 11

(i-Pr)2NEt/LiCl DBU/LiCl Cs2CO3 K2CO3 K3PO4 NaOEt t-BuONa LiHMDS t-BuOK KHMDS NaHMDS

NMP MeCN THF THF THF THF/PhMe THF/PhMe THF/PhMe THF/PhMe THF/PhMe THF/PhMe

2:1 2:1 2:1 2:1 2:1 2:1

temp. (°C)

time (h)

16 area %

80 reflux reflux reflux reflux 23 0 0 0 0 0

6.5 6.5 6.5 6.5 6.5 4.0 14.0 14.0 14.0 14.0 14.0

99.6 93.3 97.2 99.6 96.6 96.7 6.9 57.3 0.0 2.8 12.0

9 area % < < < <
99.0% HPLC area. Then the stage was set for the reduction of the double bond of 9. In our previous procedure, 40 wt % of 10%Rh/C (50% wet) was used for full conversion (Table 2, entry 1). Poisoned Pd catalysts such as SGS-10DR8 (entries 2, 3), Pd-BN catalyst9 (entries 4,5) did not give fruitful results, but 5% Pt/C was found to be promising with only 10 wt % of catalyst (50% wet) loading (entry 6). Switching the solvent from 2-propanol to ethyl acetate was effective but gave only 1.1% of debrominated 18 when reaction completed (entry 7). The catalyst loading was then optimized to 13 wt %, as decreased catalyst loading gave incomplete conversion.

dilution with toluene (same weight as the crude benzyl bromide) was critical for a clean conversion. When trimethyl phosphite was used, the reaction did not complete because the boiling point of the reagent (bp 110 °C) was too low. The removal of isopropyl bromide (bp 59−60 °C) was also important for full conversion, as the inner temperature did not reach 120 °C when the reaction was performed with refluxing. As the phosphonate 16 is an oil, it was used in the next step without further purification. The results of the base and solvent screening of the Horner− Wadsworth−Emmons (HWE) reaction are shown in Table 1. Weak bases such as i-Pr2NEt/LiCl, DBU/LiCl, Cs2CO3, K2CO3, K3PO4, or NaOEt did not give 9 even at elevated temperature (entries 1−6). Use of sodium t-butoxide at 0 °C gave the desired product but with incomplete conversion (entry 7). LiHMDS gave more than 20% HPLC area of 17 (entry 8). Although the byproduct 17 could be converted to the desired 10 under hydrogenation conditions, we noticed that the formation of 17 needed to be suppressed for the following reasons. Recrystallization of compound 9 was necessary because it was confirmed that excess triisopropyl phosphite, which was used in the previous step, is a catalyst poison.6 It was revealed that triisopropyl phosphite could be completely removed when the product 9 was recrystallized from aqueous 2-propanol. However, 17 was also removed to the mother C

DOI: 10.1021/acs.oprd.5b00207 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Solvent screening with 5% Pt/C revealed that toluene and methyl tert-butyl ether (MTBE) were also promising. As debrominated 18 was found to be efficiently removed by recrystallization from aqueous 2-propanol, it was desirable to use a solvent with a low boiling point. Toluene was omitted for this reason. MTBE (bp 55−56 °C) was better than ethyl acetate (bp 76−77 °C), but a slight difference of catalyst loading led to an increase in the formation of debrominated 18 (Figure 1).

Table 3. HPLC Area of Unreacted Starting Material 9 vs Desired Product 10 over Time entry weight ratio of water added vs dried Pt/C catalyst reaction time 3h 6h 9h note

1 0.0 (dried)

2 1.2 (54% wet)

3

4

2.9

4.5

unreacted starting material 9 vs product 10 52.7% 6.9% 0.1% 0.1% 26.9% 3.1% 0.1% 0.1% 14.4% 1.5% standard conditions

Figure 1. Catalyst loading of 5% Pt/C and HPLC area % of debrominated 18. Figure 2. Weight ratio of water to dry 5% Pt/C catalyst and HPLC area % of debrominated 18 vs desired product 10. The catalyst used in this experiment contained 54% of water, which corresponded to 1.2 weight ratio of water vs dried catalyst.

For stable yield and reproducibility, ethyl acetate was chosen as the solvent for this step. It was also found that the hydrobromide of 2 is formed (about 2% by HPLC area) during hydrogenation, presumably due to the hydrogen bromide formed through the debromination reaction. With the preliminary study, the formation of this compound was suppressed by addition of powdered K2CO3 during the hydrogenation without affecting the reaction rate. Regarding the catalyst, 13 wt % of 50% wet 5% Pt/C Nx type10 was optimal, leading to reproducible reactions which completed in about 10 h under atmospheric pressure at 25 °C. The use of Pt/C slurry in water is normally desirable for handling purposes when charging a catalyst to a reactor upon scale up. However, it was revealed that the addition of water significantly increased the formation of debrominated 18. For example, addition of two weight ratios of water vs 50% wet catalyst, which provided a good slurry of the catalyst, led to the formation of 15.4% of debrominated 18 by HPLC area %. However, this is reasonable considering that polar, protic solvents such as methanol, 2-propanol, and 1-butanol have a tendency to facilitate undesired debromination reactions (Table 2, entries 6, 7). In laboratory scale, when 50% wet 5% Pt/C was dried under reduced pressure and used in this reaction, less debrominated 18 was formed. However, this condition is not acceptable, not only because of the safely issue, but also because the reaction rate was slower than the original conditions (i.e., 50% wet catalyst with no additional water) as shown in Table 3. The water content of the catalyst positively correlates to the amount of 18 formed as shown in Figure 2. Although less water is favorable in terms of selectivity, the reaction rate was slower. We decided to use 50% wet 5% Pt/C suspended in ethyl acetate under nitrogen and charged to the reactor. After filtration of the catalyst, the solvent was switched to 2propanol, and recrystallization from aqueous 2-propanol gave 90% yield of 10 with an HPLC area of >99.0%. Although 2% of debrominated 18 was formed, it was rejected to 0.3−0.4% after

this purification. These impurities were classified into two groups as follows. The first group consisted of process-derived impurities which were present in the first generation procedure (Figure 3). Compound 17 (less than 0.10% by HPLC area %) was formed by the HWE reaction as described before, 18 (0.3−0.4%) was formed at the hydrogenation step and 19 (0.1−0.2%) was formed at the bromination step. These compounds could be easily removed by recrystallization during the following steps. One exception was 9, which was an unreacted starting material from the hydrogenation step. We decided to control 9 by HPLC in process control analysis. The second group consisted of material derived impurities (Figure 4). Compounds 20 to 24 were derived from impurities in 1-bromo-2-methoxyethane 15. Analysis of the reagent grade 15 revealed that it contained corresponding bromides that would lead to these impurities (i.e., methyl bromide, 1-bromo2-ethoxyethane, 1-bromo-2-chloroethane, 1-bromo-3-methoxypropane, and 1-bromo-2-isopropoxyethane), which also indicates that the formation of these compounds could be avoided by limiting its impurity levels. The precursor of compound 25 was considered to be formed through the reaction of 7 with the unreacted starting material 14. It was found that 14 could be easily removed to 0.03% (HPLC area %) by basic washing at workup of 6. However, the impurity 25 was still observed, indicating the presence of another pathway which gives 25. LC-MS analysis and confirmation by synthesis revealed that 0.3 to 0.9% (HPLC area %) of 26 is included in 14 (Figure 5).11 However, as long as the level of 26 in 14 did not exceed 0.9% and basic washing at workup to prepare 6 was performed, the level of 25 in 10 did not exceed 0.05% (HPLC area%). D

DOI: 10.1021/acs.oprd.5b00207 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Figure 3. First group; process derived impurities in 10.

Figure 4. Second group; material derived impurities in 10.

Condition A; SUMIPAX ODS C-212, 5 μm (6 mmφ × 150 mm). Solvent A: 0.05% aqueous trifluoroacetic acid, solvent B: methanol. Gradient program; solvent A/solvent B 50:50 to 10:90 over 20 min, hold 15 min, flow rate = 1.0 mL/min, 40 °C, UV detection at 220 nm. Condition B; SUMIPAX ODS C-212, 5 μm (6 mmφ × 150 mm). Solvent A: 0.02% aqueous trifluoroacetic acid, solvent B: 0.02% trifluoroacetic acid in methanol. Gradient program;· solvent A/solvent B, hold 25:75 for 30 min, 25:75 to 15:85 over 30 min, hold 10 min, flow rate = 0.7 mL/min, 40 °C, UV detection at 220 nm. Condition C; Kinetex (2.6 μm, 3 mmφ × 100 mm). Solvent A: 0.05% aqueous trifluoroacetic acid, solvent B: acetonitrile. Gradient program; solvent A/solvent B 90:10 to 10:90 over 24 min, hold 4 min, flow rate = 0.8 mL/min, 40 °C, UV detection at 220 nm. Condition D; YMC-Pack Pro C18 RS (3.0 μm, 4.6 mmφ × 150 mm). Solvent A: 0.02% aqueous trifluoroacetic acid, solvent B: 0.02% trifluoroacetic acid-methanol. Gradient program; solvent A/solvent B 25:75 for 30 min, then 15:85 over 30 min, hold 10 min, flow rate = 0.7 mL/min, 40 °C, UV detection at 220 nm. The purities listed were determined by area %. NMR spectra were recorded on a Bruker Avance 400 spectrometer. Chemical shifts (δ) are given in parts per million, and residual internal CHCl3 (δ 7.26) and DMSO (δ 2.50). All reactions were carried out under a nitrogen atmosphere unless otherwise mentioned. Reagents and solvents were used as obtained from commercial suppliers without further purification. Conditions for original route to (10) have already been reported.2 (4-Bromo-3-(2-methoxyethoxy)benzyl)triphenylphosphonium Bromide (8). Mp 200−203 °C (decomp.). 1H NMR (d6-DMSO, 400 MHz): 7.95−7.88 (m, 3H), 7.79−7.68 (m, 12H), 7.47 (d, J = 8.0, 0.8 Hz, 1H), 6.68 (dd, J = 2.2, 2.2 Hz, 1H), 6.58 (ddd, J = 8.0, 2.2, 2.2 Hz, 1H), 5.21 (d, J = 16.0 Hz, 2H), 3.71−3.67 (m, 2H), 3.55−3.51 (m, 2H), 3.29 (s, 3H). 13 C NMR (d6-DMSO, 100 MHz): 154.5 (d, J = 3.4 Hz), 135.1 (d, J = 2.7 Hz), 134.1 (d, J = 10.0 Hz), 133.2 (d, J = 3.2 Hz), 130.1 (d, J = 12.4 Hz), 129.0 (d, J = 8.6 Hz), 124.3 (d, J = 5.7 Hz), 117.6 (d, J = 85.2 Hz), 116.1 (d, J = 5.2 Hz), 111.1 (d, J = 5.0 Hz), 69.8, 68.1, 58.4, 28.0 (d, J = 46.3 Hz).

Figure 5. Impurity in 14.

Starting from 2-bromo-5-(hydroxymethyl)phenol 14 and 1bromo-2-methoxyethane 1512 with controlled impurities, we were able to synthesize 10 that is as pure as that obtained with the first generation procedure. To confirm the manufacturing process thus developed, a scale-up of compound 10 was performed. Starting from 10 kg of 14, the toluene solution of 7 was prepared in one batch. The solution was divided into two batches, and the subsequent steps were conducted. Thus, 6.16 and 6.32 kg of compound 10 were obtained without issue. The overall yields from compound 14 were 72 and 75% respectively, which were consistent with the average yields of laboratory experiments (71−77%).

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CONCLUSION In conclusion, the second generation process to manufacture benzyl piperidine compound 10 was demonstrated. The HWE reaction with t-BuOK proceeded with minimum isomerization of the double bond and also avoided the use of silica gel column purification. Recrystallization of the HWE product removed triisopropyl phosphite efficiently, leading to reproducible hydrogenation in the next step. Selective hydrogenation was accomplished by employing 50% wet 5% Pt/C in ethyl acetate with an adequate amounts of water, furnishing the Boc protected benzyl piperidine 10 in 90% yield. The catalyst loading was reduced from 40 wt % (10% Rh/C) to 13 wt % (5% Pt/C). It was confirmed that, by limiting the level of impurities in 2-bromo-5-(hydroxymethyl) phenol 14 and 1bromo-2-methoxyethane 15, the quality of 10 was sufficient for further clinical trials. This process was successfully scaled up to 5 kg (2 batches) in 72 and 75% yield without issue. The decarbonylative Heck reaction was found to be potential future manufacturing method.

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EXPERIMENTAL SECTION General Information. HPLC was performed on Agilent 1100 system. E

DOI: 10.1021/acs.oprd.5b00207 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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4-Bromo-3-(2-methoxyethoxy)benzoic Acid (5). A flask was charged with potassium tert-butoxide (92.2 g, 822 mmol, 3.00 equiv), N-methylpyrrolidone (300 g), and a stir bar. To this solution, 2-methoxyethanol (52.1 g, 685 mmol, 2.50 equiv) was added dropwise, and 4-bromo-3-fluorobenzoic acid (4) (60.0 g, 274 mmol) was added. The resulting mixture was heated to 90 °C for 3 h. After the reaction completed, it was cooled to 40−50 °C, and water (1200 g) was added dropwise over 30 min, followed by concentrated HCl (27.0 g, 1096 mmol, 4.00 equiv) over 30 min, during which time HF gas evolved. The resulting slurry was cooled to room temperature, filtered, and dried under reduced pressure to give (5) (65.5 g, 238 mmol) in 86.8% yield. Mp 176−178 °C. 1H NMR (d6-DMSO, 400 MHz): 13.2 (br, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.45 (dd, J = 8.4, 1.6 Hz, 1H), 4.27−4.21 (m, 2H), 3.73−3.69 (m, 2H), 3.34 (s, 3H). 13 C NMR (d6-DMSO, 100 MHz): 166.6, 154.8, 133.2, 131.7, 122.9, 116.4, 113.7, 70.2, 68.6, 58.4. 4-Bromo-3-(2-methoxyethoxy)benzoyl Chloride (11). 4-Bromo-3-(2-methoxyethoxy)-benzoic acid (5) (5.00 g, 18.2 mmol) and a stir bar were added to a flask, which was then evacuated and backfilled with nitrogen three times. Toluene (20 mL) and DMF (35 μL, 0.91 mmol, 0.05 equiv) were added via syringe, and the resulting mixture was stirred at room temperature. Oxalyl chloride (3.46 g, 27.3 mmol, 1.50 equiv) was added dropwise over 5 min via syringe, and the resulting solution was stirred for 3 h. Solvent was evaporated, and the residue was distilled under reduced pressure (1.0−0.2 mmHg, 120−140 °C) to give (11) as colorless liquid, which solidified upon standing. Mp 39−41 °C. 1H NMR (CDCl3, 400 MHz): 7.69 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 8.4, 2.0 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 4.27−4.23 (m, 2H), 3.85−3.82 (m, 2H), 3.49 (s, 3H). 13 C NMR (CDCl3, 100 MHz): 167.6, 155.7, 133.8, 133.3, 125.1, 121.5, 114.5, 70.6, 69.3, 59.5. tert-Butyl 4-(4-bromo-3-(2-methoxyethoxy)benzyl)3,6-dihydropyridine-1(2H)-carboxylate (13). 4-Bromo-3(2-methoxyethoxy)benzoyl chloride (11) (1.76 g, 6.00 mmol), palladium trifluoroacetate (90.2 mg, 0.30 mmol, 0.05 equiv), and a stir bar were added to a flask, which was then evacuated and backfilled with nitrogen three times. o-Xylene (30.0 mL, 0.2 mol/L), 1-Boc-4-methylenepiperidine (12) (1.18 g, 6.0 mmol, 1.00 equiv), and N,N-diisopropylethylamine (0.97 g, 7.50 mmol, 1.25 equiv) were added via syringe, and the resulting mixture was heated at 120 °C for 7 h. The mixture was cooled to room temperature, and 1 mol/L aq. HCl (10 mL) and water (20 mL) were added. The phases were separated, and the aqueous phase was extracted with toluene (20 mL). The combined organic phases were washed with 2.5% aq. NaOH (30 mL) and water (30 mL) and concentrated under reduced pressure below 40 °C to give an amber residue, which was used in the next step without further purification. Analytical sample was purified by silica gel column chromatography (hexane/ethyl acetate). The compound was a mixture of rotamers of the Boc group (3:2 mixture). 1 H NMR (CDCl3, 400 MHz, 3:2 mixture of rotational isomer): 7.42 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 7.4 Hz, 0.4H), 6.73 (d, J = 2.0 Hz, 1H), 6.71 (d, J = 7.2 Hz, 0.6H), 6.66 (dd, J = 8.0, 2.0 Hz, 1H), 4.76 (d, J = 7.4 Hz, 0.4H), 4.64 (d, J = 7.2 Hz, 0.6H), 4.18−4.15 (m, 2H), 3.82−3.78 (m, 2H), 3.78−3.61 (m, 1H), 3.49 (s, 3H), 3.35 (ddd, J = 13.0, 9.6, 3.2 Hz, 1H), 2.59 (dd, J = 13.0, 7.6 Hz, 1H), 2.55−2.47 (m, 1H), 2.46−2.38

(m, 1H), 1.88−1.74 (br, 1H), 1.53−1.43 (m, 1H), 1.48 (s, 9H); 13 C NMR (CDCl3, 100 MHz): 155.2, 140.9, 133.0, 125.5, 122.9, 114.7, 109.9, 108.5, 80.7, 70.9, 69.0, 59.5, 42.1, 41.0, 40.0, 33.8, 28.3, 27.7; LRMS (ESI) calcd for C15H21BrNO2 (M-Boc + H + H) 326.08, found 326.0. tert-Butyl 4-(4-bromo-3-(2-methoxyethoxy)benzyl)piperidine-1-carboxylate (10). Crude tert-butyl 4-(4bromo-3-(2-methoxyethoxy)benzyl)-3,6-dihydropyridine1(2H)-carboxylate (13) in xylene (2.56 g) was diluted with toluene (12.8 g), and the flask was evacuated and backfilled with nitrogen. The flask was then charged with 5% Pt/C (50% wet, 0.512 g), and the flask was filled with nitrogen. The flask was filled with hydrogen and stirred at room temperature for 4 h. The catalyst was filtered, and the filtrate was washed with toluene under a stream of nitrogen. 5% Pt/C (50% wet, 0.640 g) was charged to this filtrate, and hydrogenation continued another 21 h. Then the catalyst was filtered, and the filtrate was washed with toluene under nitrogen. The solvent was removed, and the residue was recrystallized from 67% aqueous 2propanol at −10 °C to give (10) (961 mg, 2.24 mmol, 97.34% with condition C) in 37.3% yield as a yellow powder. The loss in the filtrate was determined to be 7.3% by HPLC (118 mg, 0.438 mmol). Mp 89−90 °C. 1H NMR (CDCl3, 400 MHz): 7.41 (d, J = 8.0 Hz, 1H), 6.70 (d, J = 2.0 Hz, 1H), 6.62 (dd, J = 8.0, 2.0 Hz, 1H), 4.18−4.14 (m, 2H), 4.15−3.95 (br, 2H), 3.82−3.78 (m, 2H), 3.49 (s, 3H), 2.62 (dd, J = 12.2, 12.2 Hz, 2H), 2.47 (d, J = 6.8 Hz, 2H), 1.68−1.55 (m, 3H), 1.45 (s, 9H), 1.19−1.05 (m, 2H). 13 C NMR (CDCl3, 100 MHz): 155.1, 154.8, 141.1, 132.9, 123.0, 114.8, 109.7, 79.3, 70.9, 69.0, 59.5, 44.0, 42.9, 38.1, 31.9, 28.4. LRMS (APCI) calcd for C15H23BrNO2 (M-Boc + H + H) 328.09, found 328.2. (4-Bromo-3-(2-methoxyethoxy)phenyl)methanol (6). 2-Bromo-5-(hydroxymethyl)phenol (14) (10.0 kg, 49.3 mol), N-methyl piperidone (20.0 kg), and potassium carbonate (10.2 kg, 73.8 mol, 1.50 equiv) were charged and warmed to 70 °C. Then 1-bromo-2-methoxyethane (7.5 kg, 54.0 mol, 1.10 equiv) was added dropwise over 45 min, and the mixture was stirred at 70 °C for 5 h. Additional powdered (D80 < 45 μm) potassium carbonate (5.0 kg, 36.1 mol, 0.73 equiv) was added and stirred for another 2 h (HPLC condition A). Toluene (60 kg) and water (60 kg) were added, and the organic phase was separated. The aqueous phase was extracted with toluene (30 kg), and the combined organic phase was successively washed with 5% aqueous potassium carbonate solution (30 kg) and water (30 kg). The organic phase was concentrated under reduced pressure below 40 °C to a weight of 77.2 kg, which was used in the next step without further purification. 1 H NMR (CDCl3, 400 MHz): 7.47 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 1.6 Hz, 1H), 6.80 (m, 1H), 4.62 (s, 2H), 4.17−4.13 (m, 2H), 3.81−3.78 (m, 2H), 3.48 (s, 3H), 2.10 (br, 1H). 13 C NMR (CDCl3, 100 MHz): 155.4, 141.8, 133.2, 120.3, 112.0, 111.2, 70.8, 68.9, 64.6, 59.5. LRMS (ESI) calcd for C10H11BrO2 (M − H2O + H) 243.10, found 243.1. 1-Bromo-4-(bromomethyl)-2-(2-methoxyethoxy)benzene (7). (4-Bromo-3-(2-methoxyethoxy)phenyl)methanol in toluene (77.2 kg) and aqueous 47% HBr (42.4 kg, 246.3 mol) were charged to a reactor. This was heated at 70 F

DOI: 10.1021/acs.oprd.5b00207 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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°C for 2 h with vigorous stirring and then cooled to 25 °C (HPLC condition A). The aqueous phase was separated, and the organic phase was washed twice with water (38.6 kg x 2). Then the toluene solution of the title compound was concentrated under reduced pressure below 40 °C to the weight of 32.0 kg and separated into two batches. Mp 60−61 °C. 1H NMR (CDCl3, 400 MHz): 7.48 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.86 (dd, J = 8.0, 2.0 Hz, 1H), 4.43 (s, 2H), 4.21−4.17 (m, 2H), 3.83−3.79 (m, 2H), 3.49 (s, 3H); 13 C NMR (CDCl3, 100 MHz): 155.5, 138.3, 133.5, 122.6, 114.2, 112.6, 70.8, 69.0, 59.5, 32.7; Diisopropyl (4-bromo-3-(2-methoxyethoxy)benzyl)phosphonate (16). 1-Bromo-4-(bromomethyl)-2-(2methoxyethoxy)benzene (7) (16.0 kg as toluene solution) and triispropyl phosphite (5.60 kg, 26.89 mol) were charged and the solution was warmed to 120 °C over 1.5 h, during which time isopropyl bromide and toluene were distilled off (8.3 kg, HPLC condition A). The mixture was cooled to room temperature. The solution was transferred to the next reactor with toluene to give 16.65 kg of (16) as a toluene solution. 1 H NMR (CDCl3, 400 MHz): 7.43 (dd, J = 8.0, 1.2 Hz, 1H), 6.91 (dd, J = 2.0, 1.6 Hz, 1H), 6.75 (ddd, J = 8.0, 2.0, 1.6 Hz, 1H), 4.60 (m, 2H), 4.18−4.14 (m, 2H), 3.81−3.78 (m, 2H), 3.47 (s, 3H), 3.03 (d, J = 21.6 Hz, 2H), 1.27 (d, J = 6.4 Hz, 6H), 1.17 (d, J = 6.4 Hz, 6H). 13 C NMR (CDCl3, 100 MHz): 155.1 (d, J = 3.2 Hz), 133.0 (d, J = 3.0 Hz), 132.8 (d, J = 9.0 Hz), 123.6 (d, J = 7.2 Hz), 115.2 (d, J = 6.3 Hz), 110.7 (d, J = 4.6 Hz), 70.7 (d, J = 5.6 Hz), 70.6, 68.9, 59.4, 34.6 (d, J = 139.2 Hz), 24.0 (d, J = 3.8 Hz), 23.8 (d, J = 5.0 Hz). LRMS (APCI) calcd for C16H27BrO5P (M + H) 409.08, found 409.1. tert-Butyl 4-(4-bromo-3-(2-methoxyethoxy)benzylidene)piperidine-1-carboxylate (9). Diisopropyl (4-bromo-3-(2-methoxyethoxy)benzyl)phosphonate (16) in toluene (16.65 kg), tert-butyl 4-oxopiperidine-1-carboxylate (5.40 kg, 27.10 mol), and toluene (13.53 kg) were charged to a reactor. After dissolution, the mixture was cooled to −5 °C. A solution of potassium tert-butoxide (3.87 kg, 34.49 mol) in tetrahydrofuran (40.32 kg) was added to the mixture dropwise over 65 min, during which time the temperature was kept below 5 °C. After 7 h at −7 to −1 °C (HPLC area of the starting material was less than 1.0% vs the product by condition A), water (60.5 kg) was added,and phase separated. The aqueous phase was removed and the organic phase was washed with 2% sodium chloride solution (61.7 kg). To the organic layer 2-propanol (40.8 kg) was added and concentrated under reduced pressure below 40 °C to distill off 42.0 kg of solvent. Residue was adjusted to 30.28 kg with additional 2-propanol and heated to 50 °C. Water (10.1 kg) was added, and the solution was cooled to 35 °C before seed crystal (50 g) was added. Stirring was performed for 1 h, and then additional water (10.1 kg) was added dropwise over 1 h. The white slurry was cooled to 5 to 1 °C, and the crystals was filtered. The wet cake was washed three times with 67% aqueous 2-propanol (6.7 kg × 3) and dried under a stream of nitrogen at 40 °C for 17 h to give the title compound (8.70 kg, 20.41 mol, HPLC area 99.31% with condition D) in 82.9% yield over four steps from (14). Mp 80−81 °C. 1H NMR (CDCl3, 400 MHz): 7.45 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 1.6 Hz, 1H), 6.67 (dd, J = 8.0, 1.6 Hz, 1H), 6.28 (br, 1H), 4.17−4.14 (m, 2H), 3.82−3.78 (m, 2H),

3.52−3.47 (m, 2H), 3.48 (s, 3H), 3.39 (dd, J = 5.8, 5.8 Hz, 2H), 2.43 (dd, J = 5.6, 5.6 Hz, 2H), 2.31 (dd, J = 5.6, 5.2 Hz, 2H), 1.47 (s, 9H). 13 C NMR (CDCl3, 100 MHz): 155.0, 154.7, 139.4, 138.0, 132.9, 123.7, 122.8, 114.4, 110.3, 79.6, 70.9, 69.0, 59.5, 44.5, 36.1, 29.3, 28.4; (17C observed for expected 18C). LRMS (APCI) calcd for C15H21BrNO2 (M − Boc + H + H) 326.08, found 326.1. tert-Butyl-4-(4-bromo-3-(2-methoxyethoxy)benzyl)3,6-dihydropyridine-1(2H)-carboxylate (17). This compound was isolated by silica gel column chromatography. 1 H NMR (CDCl3, 400 MHz): 7.42 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 1.8 Hz, 1H), 6.65 (dd, J = 8.0, 1.6 Hz, 1H), 5.38 (br, 1H), 4.17−4.13 (m, 2H), 3.87 (br, 2H), 3.82−3.78 (m, 2H), 3.48 (s, 3H), 3.44 (t, J = 5.8 Hz, 2H), 3.24 (br, 2H), 1.97 (br, 2H), 1.45 (s, 9H). 13 C NMR (CDCl3, 100 MHz): 155.2, 154.9, 140.0, 135.6, 133.0, 122.9, 120.3, 114.6, 110.1, 79.5, 70.9, 69.0, 59.5, 43.5, 41.0, 39.8, 28.5, 28.0. LRMS (ESI) calcd for C15H21BrNO2 (M − Boc + H + H) 326.08, found 326.0. tert-Butyl-4-(4-bromo-3-(2-methoxyethoxy)benzyl)piperidine-1-carboxylate (10). tert-Butyl 4-(4-bromo-3-(2methoxyethoxy)benzylidene) piperidine-1-carboxylate (9) (7.00 kg, 16.42 mol), ethyl acetate (25.0 kg), and slurry of 5% Pt/C (50% wet, 0.91 kg) in ethyl acetate (10.0 kg) were charged to a reactor. Then the reactor was charged with hydrogen, and the pressure was maintained between 1.0 and 2.0 atm at 25 °C. Stirring was performed for 19 h, and then the atmosphere of the reactor was replaced with nitrogen. After completion of the reaction was confirmed by HPLC analysis (condition B), and the amount of H2 used, the catalyst was filtered off and washed with 2-propanol (7.0 kg). The combined filtrate was concentrated under reduced pressure below 40 °C (33.5 kg distilled off) to give a solid; then the additional 2propanol (40.0 kg) was added, and again removal of solvent (35.0 kg) gave a solid. 2-Propanol was added to the residue to adjust the weight to 24.5 kg and heated to 57 °C to dissolve. Water (8.75 kg) was added and cooled to 35 °C before seeding (40 g). The resulting slurry was allowed to stir for 1 h and cooled to 0 °C over 2 h. Stirring was performed for another 1 h before filtration. The collected crystals were washed twice with 5.3 kg of 67% aqueous 2-propanol and dried under vacuum at 50 °C for 18 h to give (10) (6.32 kg, 14.75 mol, HPLC area 99.22% with condition D) in 89.9% yield.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.5b00207. NMR spectra of important intermediates (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Ms. Norie Tsuboya for analytical support and Dr. Kiichi Kuroda for proofreading of the manuscript. G

DOI: 10.1021/acs.oprd.5b00207 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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REFERENCES

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DOI: 10.1021/acs.oprd.5b00207 Org. Process Res. Dev. XXXX, XXX, XXX−XXX