Convergent Kilogram-Scale Synthesis of Dual Orexin Receptor

Article pubs.acs.org/OPRD

Convergent Kilogram-Scale Synthesis of Dual Orexin Receptor Antagonist Mélina Girardin,† Stéphane G. Ouellet,† Danny Gauvreau,† Jeffrey C. Moore,‡ Greg Hughes,†,‡ Paul N. Devine,‡ Paul D. O’Shea,†,‡ and Louis-Charles Campeau*,†,‡ †

Global Process Chemistry, Merck Frosst Center for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Québec, Canada H9H 3L1 ‡ Global Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States S Supporting Information *

ABSTRACT: MK-6096 is an orexin receptor antagonist in clinical trials for the treatment of insomnia. Herein we describe its first kilogram-scale synthesis. Chirality on the α-methylpiperidine core was introduced in a biocatalytic transamination using a three-enzyme system with excellent enantioselectivity (>99% ee). Low diastereoselectivity of the lactam reduction was overcome by development of a camphor sulfonic acid salt formation and dr upgrade. A chemoselective O-alkylation with 5-fluoro-2hydroxypyridine was optimized and developed. Overall, 1.2 kg of MK-6069 was prepared in nine steps and 13% overall yield.

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INTRODUCTION The orexins (also named hypocretins) are hypothalamic peptides independently identified by two research teams in 1998.1 Orexins operate as neurotransmitters in the central nervous system and are involved in numerous physiological systems, most notably, sleep regulation.2 The relation between reduced orexin levels and narcolepsy has been demonstrated in rodents, dogs, and humans.3 These findings suggested the potential for an orexin receptor antagonist in the treatment of sleep disorders. Suvorexant, a dual orexin receptor antagonist, is currently in phase III clinical trials for the treatment of primary insomnia.4 Our discovery efforts identified an additional dual orexin receptor antagonist development candidate MK-6096 (1) based on an α-methylpiperidine carboxamide.5

The ketodiester 5 was screened against a variety of commercially available transaminases. It was observed that the dimethyl malonate-derived 5 was preferred to the larger diethyl malonate substrate. The Vibrio transaminase12 provided the Senantiomer (undesired), whereas the majority of the Cambrex13 enzymes and ATA-11714 were highly R-selective (desired).15 Both isopropylamine and D-alanine were screened with the R-selective enzymes as amine donors. In these initial screening experiments, only reactions using ATA-117/D-alanine reached complete conversion while affording >99% ee, and it was selected for further development. The biocatalytic transamination is described in Scheme 1. Ketone substrate 5 was treated with a combination of three enzymes to achieve full conversion to the R-amine.14 This first enzyme and the pyridoxal-5′-phosphate cofactor enabled the transfer of the amine from D-alanine to the ketodiester 5. The intermediate aminodiester 6 spontaneously cyclized to the desired piperidone 4, thus driving the equilibrium and avoiding product inhibition of the transaminase. Catalytic turnover was further ensured via Le Châtelier principle by the reduction of the pyruvate byproduct to lactate using lactate dehydrogenase (LDH) and NADH as a hydride source. A third enzyme, glucose dehydrogenase (GDH), was used to recycle NADH. The reaction was performed in water with NaH2PO4; continuous addition of 5 N NaOH was necessary to maintain a pH of 7.4, which was found to be optimal. Loading studies determined that the reaction could be successfully conducted in a concentration range of 50−75 g/L of compound 5. Higher concentration required an increase in the transaminase loading. The reaction performed best when D-alanine was near its solubility limit and glucose levels could be limited to 1.1−1.3 equiv. The synthesis for the chiral piperidine alcohol fragment 8 is presented in Scheme 2. Michael addition of dimethyl malonate

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RESULTS AND DISCUSSION To support preclinical and clinical development, we required a practical synthesis of 1 suitable for kilogram scale.6 Our retrosynthetic plan for kilogram-scale deliveries is outlined in Figure 1. Late-stage amide bond formation would allow for a convergent synthesis from the chiral piperidine fragment 3 and the acid 2. With this plan in place, the key synthetic challenge that emerged was the enantioselective preparation of the αmethylpiperidine core.7 To achieve this goal, we envisioned the enantioselective reductive amination of ketone 5 which, upon formation of the primary amine, could cyclize to afford piperidone 4 setting the α-methyl stereocenter.8 This would leave the methyl ester as a handle for installation of the side chain. Ketone 5 would be obtained from the Michael addition of readily available methyl vinyl ketone and dimethyl malonate which are inexpensive and available on multikilogram scale. Initial reductive aminations of 5 with ammonium formate and Pd/C afforded lactam 4 in a yield of ∼70% providing proof of concept for the proposed route.9 Considering strategies for an asymmetric variant we selected enantioselective biocatalytic transamination as an alternative to reductive amination.10,11 © XXXX American Chemical Society

Received: September 23, 2012

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dx.doi.org/10.1021/op3002678 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

Figure 1. Retrosynthesis of 1.

Scheme 1. Biocatalyzed transamination to piperidone 4

Scheme 2. Synthesis of chiral piperidine 8

were required to avoid the onset of a significant exotherm.16 The diastereomeric ratio of 7 was 1.7:1 following the ester reduction. The lactam could then be cleanly reduced using lithium aluminium hydride solution in THF at 50 °C. The volume-efficient Fieser workup allowed a good recovery of the highly water-soluble piperidine product 8.17 Fortunately, the diastereomeric purity could be greatly improved after this second reduction, by forming the D-(+)-camphorsulfonic acid salt 8·CSA (>40:1). We next turned our attention to the development of a robust O-selective alkylation of pyridone 13 to complete piperidine fragment 3. In support of their SAR work, the medicinal chemistry team had used a Mitsunobu reaction,18 which used

to methyl vinyl ketone provided the transamination substrate 5. Both the lactam and the ester carbonyls of the transamination product 4 needed to be reduced to afford the piperidine 8. We envisioned a chemoselective lactam reduction to take advantage of the epimerization of a piperidine ester previously described.5 However, attempts with a variety of reducing agents were unsuccessful. The concomitant reduction of both carbonyls with LiAlH4 was also briefly explored but afforded incomplete conversion even under forcing conditions. Given these results and our short timeline for delivery, we opted for a two-step reduction starting with the ester. In situ generated Ca(BH4)2 in EtOH afforded a clean reduction to the primary alcohol 7. Careful choice of solvent and control over reaction temperature B



Article

Table 1. Effects of reagents in the optimization of SN2 reaction

entry

substrate

X=

solvent

base

10:11

1 2 3 4 5 6

9a 9b 9c 9d 9d 9d

Br I OMs OTs OTs OTs

DMF DMF DMF DMF NMP NMP

Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 DBU Cs2CO3

4.4:1 3.8:1 3:1 5.6:1 3.8:1 6.8:1

Table 2. Effects of Conditions in the Optimization of SN2 Reaction

a

entry

R=

temperature (°C)

concentration (M)

10:11a

conversiona (%)

1 2 3 4 5 6 7

CBz CBz CBz CBz CBz CBz Boc

35 50 65 50 50 60 60

0.2 0.2 0.2 0.1 0.05 0.1 0.1

7.2:1 6.8:1 5.3:1 7.5:1 8.6:1 7.2:1 10.6:1

82 97 >99 99 98 99b >99c

Determined by HPLC analysis. b15g scale, 73% isolated yield (10:11 = 12:1). c45 g scale, 80% isolated yield (10:11 = 15:1).

Scheme 3. Preparation of piperidine 3

polymer-supported triphenylphosphine.5 The Mitsunobu reaction had originally been selected for its high O- vs Nchemoselectivity (typically >7:1). We decided to investigate the possibility of using an SN2 reaction.19 Having gram quantities of Cbz-protected piperidine 8 in hand from previous campaigns,20 we undertook substantial experimentation on a variety of activated species (9a−d). Results revealed that judicious choices of leaving group, solvent, and base were critical to the success of the displacement (Table 1). The tosylate leaving group was selected along with Cs2CO3 and NMP for further study of the nature of the nitrogen protecting group, which could still be changed, in addition to various reaction parameters. The effect of four reaction parameters on conversion and chemoselectivity was studied: base and pyridone 13 stoichiometries, temperature, concentration. The last two variables turned out to have the most impact on the reaction and were further studied to select

conditions for scale-up and evaluate the reaction robustness.21 Representative results from these experiments are presented in Table 2. They revealed that higher dilution and lower temperatures increased O-selectivity (entries 3−5). However, conversion significantly improved at higher temperature (entries 1−3). We also studied the effect of replacing the CBz protecting group by a Boc for ease of removal (entries 6−7). Gratifyingly, the effects observed for the SN2 with CBz-protected 9d translated well with Boc protected 12. In fact superior intrinsic O-selectivity was observed.22 Carrying out the reaction with Cs2CO3 in NMP (∼0.1 M, 20 mL/g concentration) at 60 °C, afforded 10.6:1 ratio favoring O-alkylation. In addition, while developing the isolation of 10 and 14 we were very pleased to see that the N-alkylation adducts 11 were more water-soluble in the water/NMP layer during th extractve workup, allowing for further upgrade of the O- vs N-selectivity of the product when C



Article

Scheme 4. Synthesis of biaryl acid 2

Scheme 5. Final coupling and end game for 1

ditions and coupling agents revealed that using 1-propyl phosphonic anhydride (T3P)24 provided the desired reactivity when the reactions were heated to >40 °C and an excess coupling agent was used. Using 1.25 equiv of biaryl acid 2, 3.4 equiv of T3P with DIPEA in DCM at 44 °C for 48 h provided 1 in 88% assay yield. Charcoal treatment facilitated the final recrystallization which was performed in isopropyl acetate with heptane as an antisolvent to increase recovery. Crystalline 1 was isolated with the desired purity for preclinical and clinical use (Scheme 5).

isolating in this manner. On >3-kg scale this observation led to a 15:1 isolation of 14 in 79% isolated yield. The synthesis of the chiral fragment 3 was completed with the removal of the Boc protecting group using trifluoroacetic acid in DCM. At this stage, extractive workup provided amine 3 in high purity (Scheme 3). Biaryl acid fragment 2 was prepared in a straightforward manner from the commercially available iodobenzoic acid 15 (Scheme 4). Fisher esterification with methanol was performed before palladium-catalyzed borylation. The use of pinacol borane in the latter reaction offered multiple advantages when compared with bis(pinacolato)diboron: rapid conversion, high yield, easier workup, better purity profile. The Suzuki−Miyaura coupling with 2-chloropyrimidine proceeded smoothly with PdCl2dppf·DCM (3.5 mol %) and aqueous Na2CO3 in 2methyltetrahydrofuran (2-MeTHF) at 75 °C. Finally saponification with NaOH in 2-MeTHF/water provided biaryl acid 2 which was precipitated from the basic aqueous layer by acidification with HCl in high recovery and excellent purity. Using 2-MeTHF as a cosolvent in the biaryl ester hydrolysis simplified the workup when compared with THF. The three steps from the methyl benzoate 16 to biaryl acid 2 could therefore be carried out as a through process without isolation, thus decreasing the processing time on kilogram scale. The final amidation was surprisingly challenging. Highly reactive coupling reagents such as HATU and EDC/HOBT failed to achieve more than 5% conversion to the desired amide MK-6096 (1). Activation of acid 2 with oxalyl chloride or thionyl chloride was difficult due to insolubility of the activated species in organic solvents. Direct amidation of the methyl ester of biaryl acid 2 with magnesium, lithium, and aluminum amides of 3 provided unacceptably low yields of 1 (99.7% purity). The crude solution was solvent switched to DCM and used as such in the next reaction. An analytical sample was obtained by concentration under reduced pressure. 1H NMR (400 MHz, CDCl3) 7.96 (d, J = 3.1 Hz, 1 H), 6.69 (dd, J = 9.0, 3.6 Hz, 1 H), 4.11 (dd, J = 10.5, 5.5 Hz, 1 H), 4.00 (dd, J = 10.5, 7.2 Hz, 1 H), 3.28−3.22 (m, 1 H) 2.63−2.54 (m, 1 H), 2.45 (t, J = 11.4 Hz, 1 H), 1.97−1.87 (m, 2 H), 1.74−1.68 (m, 1 H), 1.18−1.09 (m, 2 H), 1.07 (d, J = 6.3 Hz, 3 H). 13C NMR (101 MHz, CDCl3) 160.1, 155.3 (d, JCF = 246.8 Hz), 133.0 (d, JCF = 27.2 Hz), 126.5 (JCF = 21.2 Hz),

111.6, (d, JCF = 4.7 Hz), 69.5, 52.2, 50.3, 36.6, 34.1, 28.2, 22.7. IR (neat, cm−1): 2930, 1486, 1366, 1224, 826. HRMS (ESI) m/ z calcd for C12H17FN2O [M + H]+ 224.1325, found 224.1342. [α]20D +3.1 (c 3.0, CH2Cl2). 2-Iodo-5-methyl-benzoic Acid Methyl Ester (16). In a 100 L reaction vessel was charged MeOH (50 L), 2-iodo-5methylbenzoic acid (5.85 kg, 22.3 mol), and conc. sulfuric acid (595 mL, 11.2 mol). The mixture was heated to 65 °C and stirred for 18 h. It was cooled to 16 °C, and 10 N NaOH (850 mL, 21.9 mol) was added over 10 min until pH 5−6 was obtained. Caution: a pH over 9 can result in saponification during the workup. The solution was then concentrated to about 16 L, and the resulting suspension was partitioned between IPAc (40 L), water (4 L), NaHCO3 (10 L, 5 wt %), and brine (10 L, 15 wt %). The layers were cut, and the aqueous layer was extracted with IPAc (20 L). The combined organic layers were washed with brine (10 L, 15 wt %) and assayed by HPLC (6.06 kg, 98% assay yield). The crude solution was solvent switched to 2-MeTHF and used as such in the next reaction.An analytical sample was obtained by chromatography on silica gel (10% EtOAc/Hex). 1H NMR (500 MHz, CDCl3) 7.84 (d, J = 8.1 Hz, 1 H), 7.62 (d, J = 2.1 Hz, 1 H), 6.97 (dd, J = 8.1, 2.1 Hz, 1 H), 3.97−3.86 (m, 3 H), 2.33 (s, 3 H). The 1H NMR spectra obtained are in complete accord with literature precedent.28 5-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)benzoic Acid Methyl Ester (17). In a 100 L reaction vessel was charged the crude solution of iodide 16 (5.91 kg, 21.4 mol) in 2-MeTHF (35 L) and triethylamine (8.94 L, 64.1 mol). The solution was degassed with N2, and pinacol borane (4.65 L, 32.1 mol) was added over 15 min while maintaining the N2 purge. Degassing was continued for 10 min. Triotolylphosphine (325 g, 1.07 mol) and palladium(II) acetate (120 g, 0.534 mol) were added. The reaction mixture turned black, and a slow exotherm to 60 °C was observed. The reaction was heated to 77 °C and stirred for 45 min. It was cooled to room temperature before aqueous NH4Cl (26 wt %) was added over 60 min (to control gas evolution and exotherm). The addition resulted in the formation of a black precipitate. The supernatant was transferred to an extractor containing water (40 L). The remaining black slurry was filtered over Solka Floc, rinsing with MTBE (20 L). The filtrate was added to the extractor. The layers were cut, and the organic layer was assayed by HPLC (4.45 kg, 75% assay yield). The crude solution was solvent switched to 2-MeTHF and used as such in the next reaction. An analytical sample was obtained by chromatography on silica gel (gradient from 10% to 40% EtOAc/Hex). 1H NMR (500 MHz, CDCl3) 7.75 (s, 1H), 7.40 (d, J = 7.5 Hz, 1 H), 7.32 (d, J = 7.6 Hz, 1 H), 3.90 (s, 3 H), 2.37 (s, 3 H), 1.41 (s, 12 H). 13C NMR (125 MHz, CDCl3) 168.6, 139.0, 133.6, 132.5, 132.3, 129.4, 83.9, 52.2, 24.9, 21.3 (one overlapping peak, as no other peaks are detected even with prolonged scans). IR (neat, cm−1) 2980, 1718, 1347, 1058, 857. HRMS (ESI) m/z calcd for C15H21BO4 [M]+ 276.1533, found 276.1543. Mp 62.0−64.0 °C. 5-Methyl-2-pyrimidin-2-yl-benzoic Acid Methyl Ester (18). In a 100 L reaction vessel was charged the crude solution of pinacol boronate 17 (4.38 kg, 15.8 mol) in 2-MeTHF (35 L), 2-chloropyrimidine (2.18 kg, 19.0 mol), Na2CO3 (5.04 kg, 47.5 mol), and water (11.7 L). The thick slurry was degassed with N2 for 40 min after which PdCl2(dppf)·CH2Cl2 (518 g, 0.634 mol) was added. The reaction mixture was heated to 74 °C and stirred for 16 h. It was cooled to room temperature. F



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brine 15% (10 L). The organic fractions (quantitative HPLC assay at 1.65 kg) were then treated with ∼50 wt % of Darco KB (750g) for 1.75 h, then filtered on Solka Floc, and rinsed with MTBE (10 mL/g, 16.5 L, 1.559 kg, 94.5% recovery). The crude MTBE solution was charged through a 1 μm in-line filter, in a visually clean and dry 50 L RBF equipped with a mechanical stirrer, a thermocouple, a reflux condenser, and a nitrogen inlet. The reaction mixture was solvent-switched to IPAc (7.5L). The reaction mixture was warmed to 75 °C which dissolved as solids and then cooled to room temperature slowly and seeded at 45 °C with 1 (18 g), stirred overnight (16 h) at room temperature then heptane was added (9.5 L) over 60 min. The reaction mixture was aged for 1 h before cooling to 5 °C and stirred for 30 min. The suspension was then filtered and rinsed with IPAC/heptane (2 × 5L of cold 15% IPAc) and heptane (10 L). The residual beige solid was dried under a flow of nitrogen for 18 h (the product was found to be dry with 99.5% ee, >99.5% dr, Pd level of 8 ppm, and KF of 0.1). 1H spectra are in complete accord with literature precedent.5

Water (12 L) and MTBE (24 L) were added and stirring was continued for 10 min. The suspension was filtered over Solka Floc, rinsing with MTBE (4 L), water (2 × 4 L), and MTBE (4 L) again. The layers were cut, and the aqueous layer was extracted with MTBE (21.5 L). The organic layer was assayed by HPLC (2.76 kg, 76% assay yield). It was treated with Darco KB-G (1.26 kg) for 2 h and filtered over Solka Floc, rinsing with MTBE (3 × 10 L). The solution was assayed by HPLC (2.38 kg, 86% recovery, 66% overall yield, 427−493 ppm Pd and 882−934 ppm Fe). The crude solution was solvent switched to 2-MeTHF and used as such in the next reaction. An analytical sample was obtained by concentration under reduced pressure. 1H NMR (500 MHz, CDCl3) 8.78 (d, J = 4.9 Hz, 2 H), 7.97 (d, J = 7.9 Hz, 1 H), 7.51 (s, 1 H), 7.39 (d, J = 8.0 Hz, 1 H), 7.19 (t, J = 4.9 Hz, 1 H), 3.75 (s, 3 H), 2.44 (s, 3 H). 13C NMR (126 MHz, CDCl3) 170.2, 165.4, 156.8, 140.1, 135.0, 132.8, 131.4, 129.9, 129.5, 118.9, 52.1, 21.2. IR (neat, cm−1) 2953, 1725, 1556, 1417, 1305, 807. HRMS (ESI) m/z calcd for C13H12N2O2 [M]+ 228.0899, found 228.0900. 5-Methyl-2-pyrimidin-2-yl-benzoic Acid (2). A 50 L reaction vessel was charged with the crude solution of biaryl ester 18 (2.37 kg, 10.4 mol) in 2-MeTHF (15 L), water (20 L), and 10 N NaOH (2.60 L, 26.0 mol). The reaction mixture was heated to 72 °C and stirred for 1.5 h. It was cooled to room temperature and partitioned between water (4 L) and MTBE (10 L). The layers were cut, and the aqueous layer was washed MTBE (2 × 10 L). It was cooled to 7 °C and acidified to pH 1 with 12 N HCl (2.3 L), keeping the temperature below 10 °C. The precipitate was recovered by filtration and rinsed with water (2 × 7 L, 0 °C), 15% MTBE/heptane (7 L, 0 °C), 15% toluene/heptane (7 L, 0 °C), MTBE (3.5 L), and heptane (2 × 7 L). A light-beige solid was obtained (2.15 kg, 97% yield, 99.2% purity, 264 ppm Pd and 19.7 ppm Fe). 1H NMR (500 MHz, DMSO-d6) 12.65 (s, 1 H), 8.85−8.82 (m, 2 H), 7.78 (dd, J = 7.9, 2.3 Hz, 1 H), 7.49−7.37 (m, 3 H), 2.40 (s, 3 H). 13C NMR (101 MHz, DMSO-d6) 170.1, 165.1, 157.1, 139.4, 135.1, 134.2, 130.8, 129.9, 129.0, 119.4, 20.7. IR (neat, cm−1) 1702, 1575, 1417, 1204, 784. HRMS (ESI) m/z calcd for C12H10N2O2 [M]+ 214.0742, found 214.0740. mp 227.6− 228.1 °C (followed by rapid degradation). ((2R,5R)-5-(((5-Fluoropyridin-2-yl)oxy)methyl)-2methylpiperidin-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone (1). Amine 3 (1 kg, 4.46 mol) was charged along with DCM (11 L) in a 50 L flask equipped with a thermocouple and mechanical stirrer. DIPEA (2 L, 11.45 mol) was added, and then the biaryl acid 2 (1.22 kg, 5.67 mol) was added to this stirring solution. This solution was cooled with an ice bath (12 °C). To this stirring solution was added T3P (7.87 L, 13.38 mol) through an addition funnel at

Convergent Kilogram-Scale Synthesis of Dual Orexin Receptor

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