Insomnia is characterized by difficulties in initiating,maintaining, or obtaining good quality sleep and is a prevalent public health problem affecting large segments of the population on a situational,recurrent,or chronic basis. The estimated annual costs associated with insomnia number into the billions of dollars ^{[1, 2, 3, 4]}. Over the past several years,the orexin system has gained major popularity as a novel mechanism for the control of sleep disorders due to its highly conserved nature and its ability to regulate arousal and wakefulness ^[5]. Orexin A (OX-A) and orexin B (OX-B) (the hypocretins),neuropeptides produced by neurons in the hypothalamus,are derived from the same precursor protein ^{[6, 7]}. The relationship between reduced orexin levels and narcolepsy has been demonstrated in rodents,dogs,and humans ^[8]. These studies suggest the potential of an orexin receptor antagonist in the treatment of sleep disorders. Suvorexant (Fig. 1), a dual orexin receptor antagonist developed by Merck & Co. ^[9] completed phase III clinical trials for the treatment of primary insomnia.

Fig. 1

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Fig. 1. Structure of suvorexant.

In recent years,several protocols have been developed for the synthesis of suvorexant (Scheme 1). The original synthetic route was developed by Cox and coworkers in 2010 ^[9]. Central to this approach was the synthesis of the core diazepane R-11,which was afforded by a preparative chiral high-performance liquid chromatography (HPLC) separation of orthogonally protected racemic 11. Removal of the Boc protecting group,coupling with acid 5,and hydrogenolysis of the Cbz group yielded compound 9. Finally, treatment of 9 with 2,5-dichloro-1,3-benzoxazole 8 in the presence of potassium carbonate completed the synthesis of 1.

Scheme 1

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Scheme 1. Reported synthetic route of suvorexant

The large-scale synthesis of suvorexant was reported in 2011 ^[10]. The key intermediate,R-isomer 12 could be achieved via the classical resolution,while the racemic 12 was prepared through the reductive amination of 13,and 1 was accomplished followed by condensation with 5. However,in addition to the desired product racemic 12 it was found that impurities 15 and 16 were generated ^[10] (Scheme 1).

Strotman et al. ^[11] offered the first asymmetric reductive amination of a dialkyl ketone with an alkyl amino. The desired diazepane ring R-12 was produced in 97% yield and high enantiopurity (94.5% ee) by mediation with a novel Ru-based transfer hydrogenation catalyst.

More recently,Mangion et al. ^[12] reported yet another strategy for the synthesis of suvorexant. The transamination of compound 14 was conducted with a biological enzyme (i.e.,CDX-017),resulting in good conversion yields and high enantiopurity (>99% ee). As a part of our continuing interest in developing practical and efficient processes for the synthesis of active pharmaceutical ingredients (APIs) and related intermediates,the current study describes recent efforts to develop a practical route to synthesizing suvorexant.

R-3-aminobutyric acid and compound 8 were purchased from commercial suppliers. Melting points were determined in open capillary tubes and are uncorrected. The reactions were monitored by thin-layer chromatography to detect the completion of the reaction. NMR spectra were recorded on a Bruker Ascend^TM 600 spectrometer. Mass spectra were provided on Agilent 1100 LC-MS.

To a solution of methyl 2-(benzylamino)acetate (compound 10, 50.14 g,0.28 mol),(R)-3-((tert-butoxycarbonyl)amino)butanoic acid (50.75 g,0.25 mol),1-hydroxy-1H-benzotriazole (41.88 g, 0.31 mol),and dry triethylamine (37.95 g,0.38 mol) in 320 mL of DMF was added EDC hydrochloride (57.51 g,0.30 mol),and the reaction was stirred for 5 h at room temperature. The reaction was partitioned between EtOAc and 10% aqueous citric acid,the layers were separated and the organic was washed with 5% aqueous Na₂CO₃,then with brine,dried over MgSO₄ and concentrated by rotary evaporation. The residue was recrystallized from a mixture solvent (PE:EtOAc = 2:1) to provide compound 3 as a white solid, 83.01 g in 91% yield. Mp: 107 ℃,[α]D 25 22.0 (c 0.52,MeOH). 1H NMR (600 MHz,DMSO-d₆): δ 7.38-7.23 (m,5H),6.73-6.72 (d,1H, J = 6 Hz),4.75-4.43 (m,2H),4.31-3.95 (m,2H),3.89-3.87 (t,1H, J = 12 Hz),3.64-3.62 (d,3H,J = 12 Hz),2.64-2.50 (m,1H),2.37- 2.23 (m,1H),1.38-1.37 (d,9H,J = 6 Hz),1.08-1.06 (m,3H); MS (ESI) m/z: 365.20 [M+H]⁺. HR-MS(ESI): m/z [M+H] calcd. for C₁₉H₂₈N₂O₅: 365.2071; found: 365.2066.

A solution of compound 3 (15.93 g,43.74 mmol) in 10 mL EtOAc was added 150 mL 45% HCl/EtOAc and the reaction was stirred for 4 h. The solvents were removed by rotary evaporation,and the residue was basified with saturated aqueous NaHCO₃,and extracted with CH₂Cl₂. The organic extracts were concentrated. The residue was dissolved in 150 mL of dehydrated MeOH, treated with CH₃ONa (2.84 g,52.49 mmol),and stirred at room temperature overnight (N2 protected,slightly exothermic). The reaction was cooled to room temperature and quenched with aqueous NH₄Cl. Most of the solvent was removed and the reaction was then dumped into a separatory funnel containing 5% aqueous Na₂CO₃ and extracted with CH₂Cl₂ three times. The organic layers were combined,dried over MgSO₄,and concentrated to provide compound 4 as a white solid 9.50 g in 94% yield. Analytical HPLC analysis carried out on Chiralpak AD column (4.6 mm × 250 mm) with 60% EtOH in hexanes (containing 0.1% diethylamine as a modifier),flow rate of 1 mL/min,indicated that intermediate (R)-4 was of >99% ee. Mp: 122-123 ℃. [α]D²⁵ 33.5 (c 0.56,MeOH). ¹H NMR (600 MHz,DMSO-d₆): δ 7.77-7.76 (bd,1H,J = 6 Hz),7.33-7.25 (m,5H),4.59-4.53 (m,2H),4.10- 4.02 (m,2H),3.65-3.62 (m,1H),2.93-2.90 (m,1H),2.76-2.72 (m,1H), 1.14-1.13 (d,3H,J = 6 Hz); ¹³C NMR (150 MHz,DMSO-d₆): δ 171.1, 168.4,138.1,128.9,128.0,127.7,53.1,50.6,46.5,40.5,23.3. MS (ESI) m/z: 233.10 [M+H]⁺. HR-MS(ESI): m/z [M+H] calcd. for C₁₃H₁₆N₂O₂: 233.1285; found: 233.1289.

A solution of compound 4 (1.40 g,6.0 mmol) in 60 mL THF at 0 ℃ was treated with LiAlH₄ (1.36 g,36.0 mmol) in batches. The reaction was slowly warmed to room temperature and stirred for another 4 h. The reaction was then cooled to -10 ℃ and was carefully quenched with 1.5 mL water,then NaOH (1.5 mL,15%) followed by an additional 4.5 mL of water. A portion of MgSO₄ was added and the mixture was stirred for 1 h before filtered. The filtrate was concentrated to provide light yellow oil 1.10 g in 88% yield. [α]D²⁵ -5.9 (c 1.00,CHCl3),ee >99%,Analytical analysis was performed on Chrom Tech chiral-AGP column (150 mm × 4 mm) with 99% 1 mol/L ammonium dihydrogen phosphate and 1% acetonitrile,at flow rate of 0.5 mL/min with column temperature of 40 ℃. ¹H NMR (600 MHz,DMSO-d₆): δ 7.32-7.20 (m,5H),3.57 (s, 2H),3.48 (bs,1H),2.99-2.95 (m,1H),2.86-2.82 (m,1H),2.72-2.68 (m,1H),2.65-2.61 (m,1H),2.58-2.49 (m,3H),1.75-1.70 (m,1H), 1.46-1.41 (m,1H),1.01-1.00 (d,3H,J = 6 Hz); ¹³C NMR (150 MHz, DMSO-d₆): δ 140.1,128.9,128.5,127.1,62.5,58.8,52.7,52.6,47.0, 37.5,23.9. MS (ESI) m/z: 205.10 [M+H]⁺. HR-MS(ESI): m/z [M+H] calcd. for C₁₃H₂0N₂: 205.1699; found: 205.1692.

To a solution of compound 6 (2.40 g,11.76 mmol),compound 5 (2.86 g,14.11 mmol),1-hydroxy-1H-benzotriazole (1.90 g, 14.11 mmol),and dry triethylamine (3.56 g,35.28 mmol) in 18 mL of dry DMF was added EDC hydrochloride (2.70 g, 14.11 mmol),and the reaction was stirred 2 h at room temperature. The reaction was partitioned between EtOAc and saturated aqueous NaHCO₃,the layers were separated and the organic was added to aqueous citric acid stirring for 1 h. Water was added and the mixture was partitioned. Combined the water layers and added saturated aqueous Na₂CO₃ to regulate pH > 9,then extracted with three portions of EtOAc. The organic layers were combined,dried over MgSO₄ and concentrated by rotary evaporation to provide compound 7 as a white power 4.30 g in 93% yield. Mp: 108-109 ℃, [α]D²⁵-58.4 (c 1.01,MeOH). 1HNMR(600 MHz,DMSO-d₆): δ 8.00- 7.76 (m,3H),7.37-7.17 (m,7H),4.40-4.09 (m,1H),3.63-3.48 (m, 2H),3.44-3.02 (m,3H),2.82-2.75 (m,1H),2.63-2.47 (m,1H), 2.63-2.14 (m,5H),2.02- 1.63 (m,2H),1.17-0.99 (m,3H); MS (ESI) m/z: 390.30 [M+H]⁺. HR-MS(ESI): m/z [M+H] calcd. for C₂₃H₂₇N₅O: 390.2288; found: 390.2281.

Compound 7 (5.86 g,15.05 mmol) was dissolved in 58 mL MeOH. After a portion of 10% Pd/C was added,the reaction was stirred for 4 h under H2 atmosphere at room temperature. The reaction was filtered through a pad of celite and the filtrate was concentrated to provide compound 9 as a white solid 4.01 g in 89% yield. Mp: 119-121 ℃,^[a]D 26 -14.4 (c 1.00,MeOH)). ¹H NMR (600 MHz,DMSO-d₆): δ 8.24-8.02 (m,2H),7.88-7.29 (m,3H), 4.42-2.50 (m,7H),2.41 (s,3H),2.24-1.98 (m,2H),1.17-0.99 (m, 3H); ¹³C NMR (150 MHz,DMSO-d₆): δ 168.6,138.3,136.9,134.1, 131.1,129.2,128.3,122.5,52.6,49.1,44.4,43.1,37.8,20.8,20.6. MS (ESI) m/z: 300.20 [M+H]⁺. HR-MS(ESI): m/z [M+H] calcd. for C₁₆H₂₁N₅O: 300.1819; found: 300.1812.

To compound 8 (0.56 g,3 mmol) in 10 mL dry DMF was added TEA (0.91 g,9 mmol) and compound 9 (0.89 g,3 mmol),the mixture was stirred at 75 ℃ for 2 h. After cooling to room temperature,the reaction was diluted with EtOAc,washed with saturated aqueous NaHCO₃,water,brine and dried over MgSO₄. The residue was recrystallized from i-PrOH/EtOAc to provide a white solid 1.20 g in 90% yield. Mp: 149-150 ℃,[α]D²⁵ -11.6 (c 1.00,MeOH). Analytical HPLC analysis carried out on a Chiralpak AD column (4.6 mm × 250 mm) with 60% EtOH in hexanes (containing 0.1% diethylamine as a modifier) at a flow rate of 1 mL/min,indicated that intermediate (R)-4 was of >99% ee. Mp: 153 ℃,[α]D²⁵ -11.7 (c 1.00,MeOH) ^[10],¹H NMR (600 MHz, DMSO-d₆): δ 8.05-7.88 (m,2H),7.82-7.78 (m,1H),7.42-7.25 (m, 2H),7.06-7.00 (m,1H),4.29-4.06 (m,1H),4.01-3.72 (m,2H), 3.66-3.49 (m,2H),2.10 (s,3H),2.06-2.01 (m,1H),1.50 (m,1H), 1.78-1.50 (m,1H),1.14-1.13 (d,3H,J = 6 Hz); ¹³C NMR (150 MHz, DMSO-d₆): δ 168.5,163.4,147.8,145.2,138.4,136.6,136.5,134.1, 130.8,129.8,128.6,122.8,120.1,115.6,110.2,52.3,48.3,45.1,43.7, 35.6,20.9,17.2. MS (ESI) m/z: 451.20 [M+H]⁺. HR-MS(ESI): m/z [M+H] calcd. for C₂₃H₂₃C_lN₆O₂: 451.1644; found: 451.1639.

The retrosynthetic procedure in Scheme 2 shows that the intermediate 6 can be converted to suvorexant via condensation, deprotection,and substitution. A benzyl moiety was selected as the protecting group,and the target molecule was achieved by the substitution of benzoxazole. Condensation of 6 and 5 resulted in amide 7.

Scheme 2

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Scheme 2. Retro-synthesis of suvorexant.

The synthesis begins with the protection of R-3-aminobutyric acid (Scheme 3). In accordance with a previously published procedure ^[13],triethylamine-assisted (Boc)₂O protection was performed to furnish intermediate 2 in 90% yield. The Boc-amino acid (2) was then condensed with intermediate 10 under 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole (HOBt) conditions to give compound 3 with 91% yield. The lactam ring 4 was then created with 94% yield by deprotection with gaseous hydrogen chloride (HCl) in ethyl acetate (EtOAc) followed by intramolecular cyclization with sodium methoxide (CH₃ONa). Reduction of the lactam (4) with lithium aluminum hydride at ambient temperature in anhydrous tetrahydrofuran (THF) gave the chiral diazepane (6) in good yield (88%) and high enantiopurity (>99% ee).

Scheme 3

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Scheme 3. Synthesis of 6.

Preparation of the chiral diazepane ring is the key in the synthesis of diazepane 6. This step was first conducted via Boc deprotection with gaseous HCl in EtOAc followed by intramolecular cyclization with 1.5 equiv. of CH₃ONa at 58 ℃. However,the yield of this process was less than 50%. The reaction temperature and the amount of CH₃ONa were varied as shown in Tables 1 and 2, respectively,in order to improve cyclization yield. The results in Table 1 show that yields increased with decreasing reaction temperature. Thus,reactions were run at room temperature to optimize the amount of CH₃ONa added to the reaction mixture. The results in Table 2 show that increasing the amount of CH₃ONa decreased yields. The best results (94% yield,entry 4) were observed when the reaction was run at room temperature with 1.2 equiv. of CH₃ONa.

Table 1

Table 1 Optimization of reaction temperature for the cyclization.a

Table 1 Optimization of reaction temperature for the cyclization.a

Table 2

Table 1 Optimization of the amount of sodium methoxide.a

Table 2 Optimization of the amount of sodium methoxide.a

Condensation of diazepane 6 with triazole acid 5 which was synthesized from commercially available benzoic acid 10 to provide compound 7 with 93% yield. The benzyl protecting group was removed after catalytic hydrogenation at ambient pressure and room temperature on 10% Pd/C to produce a white solid 9 with 89% yield. There are no other impurities generated in the process of preparation of compound 9. Finally,9 was coupled with 2, 5-dichloro-1,3-benzoxazole 8 to yield suvorexant (Scheme 4). After a typical workup,the crude product was recrystallized from i-PrOH/EtOAc,and suvorexant was isolated in 90% yield with 99% HPLC purity and >99% ee.

Scheme 4

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Scheme 4. Synthesis of suvorexant.

In summary,a practical procedure was devised for the synthesis of suvorexant from available raw materials. The chiral group was introduced via intramolecular cyclization of a chiral diazepane derivative prepared from R-3-aminobutyric acid. The synthetic improvements described herein led to the synthesis of suvorexant in an improved 31% overall yield with eight steps. The uses of biological enzyme,classical resolution and chiral HPLC separation have been avoided. Moreover,the target compounds at each step maintained a high level of enantiopurity. Thus,the high yields,high enantiopurity,and mild reaction conditions described herein provide a new method to synthesis of suvorexant.