Facile synthesis of suvorexant, an orexin receptor antagonist, via a chiral diazepane intermediate

Article abstract of DOI:10.1016/j.cclet.2014.09.020

A facile synthesis of suvorexant, an orexin receptor antagonist, is described. The key intermediate 6 was prepared from R-3-aminobutyric acid through protection, condensation, deprotection, cyclization, and hydrogenation steps. The title product was obtained with a total yield of 31% (>99% ee) after eight linear steps using commercially available raw materials.

Full text of DOI:10.1016/j.cclet.2014.09.020

G Model
CCLET 3101 1–5
Chinese Chemical Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
1
2
Original article
3
4
Facile synthesis of suvorexant, an orexin receptor antagonist,
via a chiral diazepane intermediate
a,b,1
a,1
b
b
a,b,
5
Q1 Yin Chen
, Yan Zhou , Jun-Hong Li , Jia-Quan Sun , Gui-Sen Zhang
*
a
6
7
8
Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology,
Wuhan 430074, China
b
Jiangsu Nhwa Pharmaceutical Co., Ltd., Xuzhou 221116, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A facile synthesis of suvorexant, an orexin receptor antagonist, is described. The key intermediate 6 was
prepared from R-3-aminobutyric acid through protection, condensation, deprotection, cyclization, and
hydrogenation steps. The title product was obtained with a total yield of 31% (>99% ee) after eight linear
steps using commercially available raw materials.
Received 8 July 2014
Received in revised form 6 August 2014
Accepted 5 September 2014
Available online xxx
ß 2014 Gui-Sen Zhang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Keywords:
Synthesis
Suvorexant
Chiral diazepane
9
1
0
1. Introduction
In recent years, several protocols have been developed for the 28
synthesis of suvorexant (Scheme 1). The original synthetic route 29
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Insomnia is characterized by difficulties in initiating, main-
taining, 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–
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 hypo-
thalamus, 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.
was developed by Cox and coworkers in 2010 [9]. Central to this 30
approach was the synthesis of the core diazepane R-11, which was 31
afforded by a preparative chiral high-performance liquid chroma- 32
tography (HPLC) separation of orthogonally protected racemic 33
11. Removal of the Boc protecting group, coupling with acid 5, and 34
hydrogenolysis of the Cbz group yielded compound 9. Finally, 35
treatment of
9
with 2,5-dichloro-1,3-benzoxazole
8
in the 36
37
presence of potassium carbonate completed the synthesis of 1.
The large-scale synthesis of Suvorexant was reported in 2011 38
[10]. The key intermediate, R-isomer 12 could be achieved via the 39
classical resolution, while the racemic 12 was prepared through 40
the reductive amination of 13, and 1 was accomplished followed by 41
condensation with 5. However, in addition to the desired product 42
racemic 12 it was found that impurities 15 and 16 were generated 43
[10] (Scheme 1).
44
Strotman et al. [11] offered the first asymmetric reductive 45
amination of a dialkyl ketone with an alkyl amino. The desired 46
diazepane ring R-12 was produced in 97% yield and high 47
enantiopurity (94.5% ee) by mediation with a novel Ru-based 48
transfer hydrogenation catalyst.
49
More recently, Mangion et al. [12] reported yet another strategy 50
for the synthesis of suvorexant. The transamination of compound 51
*
Corresponding author at: Systems Biology Theme, Department of Biomedical
Q2
Engineering, College of Life Science and Technology, Huazhong University of
Science and Technology, Wuhan 430074, China.
1
4 was conducted with a biological enzyme (i.e., CDX-017), 52
resulting in good conversion yields and high enantiopurity 53
(>99% ee). 54
E-mail address: gszhang@mail.hust.edu.cn (G.-S. Zhang).
1
These authors contributed to this work equally.
http://dx.doi.org/10.1016/j.cclet.2014.09.020
1
001-8417/ß 2014 Gui-Sen Zhang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Please cite this article in press as: Y. Chen, et al., Facile synthesis of suvorexant, an orexin receptor antagonist, via a chiral diazepane
intermediate, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.09.020

G Model
CCLET 3101 1–5
2
Y. Chen et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
of DMF was added EDC hydrochloride (57.51 g, 0.30 mol), and the
74
75
76
77
78
79
80
81
82
83
84
85
86
87
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
2 3 4
Na CO , then with brine, dried over MgSO 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,
2
D
5
1
8
3.01 g in 91% yield. Mp: 107 8C, [
a
]
22.0 (c 0.52, MeOH). H
NMR (600 MHz, DMSO-d ): 7.38–7.23 (m, 5H), 6.73–6.72 (d, 1H,
6
d
Fig. 1. Structure of suvorexant.
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
5
5
5
5
5
5
6
7
8
9
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.
19 28 2 5
C H N O : 365.2071; found: 365.2066.
2.2. Synthesis of (R)-4-benzyl-7-methyl-1,4-diazepane-2,5-dione (4)
88
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
89
90
91
6
0
2. Experimental
residue was basified with saturated aqueous NaHCO
extracted with CH Cl . The organic extracts were concentrated.
The residue was dissolved in 150 mL of dehydrated MeOH, treated
with CH ONa (2.84 g, 52.49 mmol), and stirred at room tempera-
ture overnight (N protected, slightly exothermic). The reaction
was cooled to room temperature and quenched with aqueous
NH Cl. Most of the solvent was removed and the reaction was then
dumped into a separatory funnel containing 5% aqueous Na CO
and extracted with CH Cl three times. The organic layers were
combined, dried over MgSO and concentrated to provide
3
,
and
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
6
6
6
6
6
6
6
1
2
3
4
5
6
7
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
600 spectrometer. Mass spectra were provided on Agilent 1100 LC-
MS.
2
2
3
2
TM
4
2
3
2
2
6
6
8
9
2.1. Synthesis of (R)-methyl 2-(N-benzyl-3-((tert-
4
,
butoxycarbonyl)amino)-butanamido)acetate (3)
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
70
71
72
73
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
2
5
was of >99% ee. Mp: 122–123 8C. [
a
]
D
33.5 (c 0.56, MeOH).
1
H NMR (600 MHz, DMSO-d ): d 7.77–7.76 (bd, 1H, J = 6 Hz),
6
Scheme 1. Reported synthetic route of suvorexant.
Please cite this article in press as: Y. Chen, et al., Facile synthesis of suvorexant, an orexin receptor antagonist, via a chiral diazepane
intermediate, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.09.020

G Model
CCLET 3101 1–5
Y. Chen et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
Scheme 2. Retro-synthesis of suvorexant.
Scheme 3. Synthesis of 6.
3
108
109
110
111
112
113
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,
compound 7 as a white power 4.30 g in 93% yield. Mp: 108–109 8C, 148
2
5
1
[
a
]
D
À58.4 (c 1.01, MeOH). H NMR (600 MHz, DMSO-d
6
): d 8.00– 149
13
3H, J = 6 Hz); C NMR (150 MHz, DMSO-d
6
):
d
171.1, 168.4, 138.1,
7.76 (m, 3H), 7.37–7.17 (m, 7H), 4.40–4.09 (m, 1H), 3.63–3.48 (m, 150
2H), 3.44–3.02 (m, 3H), 2.82–2.75 (m, 1H), 2.63–2.47 (m, 1H), 151
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 C13
H
16
N
2
O
2
:
2.63–2.14 (m, 5H), 2.02– 1.63 (m, 2H), 1.17–0.99 (m, 3H); MS (ESI) 152
+
233.1285; found: 233.1289.
m/z: 390.30 [M+H] . HR-MS(ESI): m/z [M+H] calcd. for C23
3
H
27
5
N O: 153
154
90.2288; found: 390.2281.
1
14
2.3. Synthesis of (R)-1-benzyl-5-methyl-1,4-diazepane (6)
2.5. Synthesis of (R)-(7-methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H- 155
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
A solution of compound 4 (1.40 g, 6.0 mmol) in 60 mL THF at
0 8C was treated with LiAlH (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 À10 8C and was
carefully quenched with 1.5 mL water, then NaOH (1.5 mL, 15%)
1,2,3-triazol-2-yl)phenyl)methanone (9) 156
4
Compound 7 (5.86 g, 15.05 mmol) was dissolved in 58 mL 157
MeOH. After a portion of 10% Pd/C was added, the reaction was 158
2
stirred for 4 h under H atmosphere at room temperature. The 159
followed by an additional 4.5 mL of water. A portion of MgSO
4
was
reaction was filtered through a pad of celite and the filtrate was 160
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%
concentrated to provide compound 9 as a white solid 4.01 g in 89% 161
2
6
1
yield. Mp: 119–121 8C, [
a
]
D
À14.4 (c 1.00, MeOH)). H NMR 162
2
5
yield. [
a
]
D
À5.9 (c 1.00, CHCl
3
), ee >99%, Analytical analysis was
(600 MHz, DMSO-d ):
6
d
8.24–8.02 (m, 2H), 7.88–7.29 (m, 3H), 163
performed on Chrom Tech chiral-AGP column (150 mm  4 mm)
4.42–2.50 (m, 7H), 2.41 (s, 3H), 2.24–1.98 (m, 2H), 1.17–0.99 (m, 164
1
3
with 99% 1 mol/L ammonium dihydrogen phosphate and 1%
6
3H); C NMR (150 MHz, DMSO-d ): d 168.6, 138.3, 136.9, 134.1, 165
acetonitrile, at flow rate of 0.5 mL/min with column temperature of
131.1, 129.2, 128.3, 122.5, 52.6, 49.1, 44.4, 43.1, 37.8, 20.8, 20.6. MS 166
1
+
40 8C. H NMR (600 MHz, DMSO-d
6
):
d
7.32–7.20 (m, 5H), 3.57 (s,
(ESI) m/z: 300.20 [M+H] . HR-MS(ESI): m/z [M+H] calcd. for 167
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),
C
16
H
21
N
5
O: 300.1819; found: 300.1812.
168
13
1.46–1.41 (m, 1H), 1.01–1.00 (d, 3H, J = 6 Hz); C NMR (150 MHz,
DMSO-d ): 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 C13 : 205.1699; found: 205.1692.
Table 1
6
d
a
+
Optimization of reaction temperature for the cyclization.
b
H
20
N
2
Entry
T (8C)
Yield (%)
1
2
3
r.t.
72.7
49.1
35.5
1
1
34
35
2.4. Synthesis of (R)-(4-benzyl-7-methyl-1,4-diazepan-1-yl)(5-
50
Reflux
methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (7)
a
The amount of sodium methoxide: 1.5 equiv.
Isolated yields.
b
136
137
138
139
140
141
142
143
144
145
146
147
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 tempera-
ture. The reaction was partitioned between EtOAc and saturated
Table 2
a
Optimization of the amount of sodium methoxide.
b
Entry
MeONa (equiv.)
Yield (%)
1
2
3
4
5
2
61.6
70.8
73.4
94.2
89.5
3
aqueous NaHCO , the layers were separated and the organic was
1.8
1.5
1.2
1
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 Na
three portions of EtOAc. The organic layers were combined, dried
over MgSO and concentrated by rotary evaporation to provide
2 3
CO to regulate pH > 9, then extracted with
a
Room temperature.
b
Isolated yields.
4
Please cite this article in press as: Y. Chen, et al., Facile synthesis of suvorexant, an orexin receptor antagonist, via a chiral diazepane
intermediate, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.09.020

G Model
CCLET 3101 1–5
4
Y. Chen et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
Scheme 4. Synthesis of suvorexant.
1
69
2.6. Synthesis of suvorexant
deprotection with gaseous HCl in EtOAc followed by intramolecu-
lar cyclization with 1.5 equiv. of CH ONa at 58 8C. However, the
yield of this process was less than 50%. The reaction temperature
and the amount of CH ONa 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
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
3
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
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 8C for 2 h. After cooling to room
temperature, the reaction was diluted with EtOAc, washed with
3
saturated aqueous NaHCO
MgSO . The residue was recrystallized from i-PrOH/EtOAc to
provide a white solid 1.20 g in 90% yield. Mp: 149–150 8C, [
3
, water, brine and dried over
4
optimize the amount of CH
results in Table 2 show that increasing the amount of CH
3
3
ONa added to the reaction mixture. The
2
5
a
]
D
ONa
À11.6 (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:
decreased yields. The best results (94% yield, entry 4) were
observed when the reaction was run at room temperature with
3
1.2 equiv. of CH ONa.
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.
2
5
1
153 8C, [
a
):
]
D
À11.7 (c 1.00, MeOH) [10], H NMR (600 MHz,
DMSO-d
6
d
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),
13
1.78–1.50 (m, 1H), 1.14–1.13 (d, 3H, J = 6 Hz); C NMR (150 MHz,
DMSO-d ): 168.5, 163.4, 147.8, 145.2, 138.4, 136.6, 136.5, 134.1,
6
d
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 C23
6 2
H23ClN O : 451.1644; found: 451.1639.
1
90
3. Results and discussion
4. Conclusions
236
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
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.
In summary, a practical procedure was devised for the
237
238
239
240
241
242
243
244
245
246
247
248
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
The synthesis begins with the protection of R-3-aminobutyric
acid (Scheme 3). In accordance with a previously published
2
procedure [13], triethylamine-assisted (Boc) O 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
described herein provide
suvorexant.
a new method to synthesis of
References
249
[
[
1] A.N. Vgontzas, A. Kales, Sleep and its disorders, Annu. Rev. Med. 50 (1999) 387–
00.
250
251
252
253
254
255
256
257
3
sodium methoxide (CH ONa). Reduction of the lactam (4) with
4
lithium aluminum hydride at ambient temperature in anhydrous
tetrahydrofuran (THF) gave the chiral diazepane (6) in good yield
(88%) and high enantiopurity (>99% ee).
Preparation of the chiral diazepane ring is the key in the
synthesis of diazepane 6. This step was first conducted via Boc
2] E.E. Matthews, J. Todd Arnedt, M.S. McCarthy, L.J. Cuddihy, M.S. Aloia, Adherence
to cognitive behavioral therapy for insomnia: a systematic review, Sleep Med.
Rev. 17 (2013) 453–464.
3] P.K. Kondamudi, R. Malayandi, C. Eaga, D. Aggarwal, Drugs as causative agents and
therapeutic agents in inflammatory bowel disease, Acta Pharm. Sin. B 5 (2013)
289–296.
[
Please cite this article in press as: Y. Chen, et al., Facile synthesis of suvorexant, an orexin receptor antagonist, via a chiral diazepane
intermediate, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.09.020

G Model
CCLET 3101 1–5
Y. Chen et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
5
2
2
2
2
2
2
2
2
2
2
2
2
2
58
59
60
61
62
63
64
65
66
67
68
69
70
[4] D. Leger, V. Bayon, Societal costs of insomnia, Sleep Med. Rev. 14 (2010) 379–389.
[5] C.R. Hopkins, ACS Chemical neuroscience molecule spotlight on suvorexant, ACS
Chem. Neurosci. 3 (2012) 647–648.
[6] T. Sakurai, A. Amemiya, M. Ishii, et al., Orexins and orexin receptors: a family of
hypothalamic neuropeptides and G protein coupled receptors that regulate
feeding behavior, Cell 92 (1998) 573–585.
[7] L. de Lecea, T.S. Kilduff, C. Peyron, et al., The hypocretins: hypothalamus-specific
peptides with neuroexcitatory activity, Proc. Natl. Acad. Sci. U. S. A. 95 (1998)
322–327.
[8] M. Hungs, E. Mignot, Hypocretin/orexin, sleep and narcolepsy, BioEssay 23 (2001)
397–408.
yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the 271
treatment of insomnia, J. Med. Chem. 53 (2010) 5320–5332.
272
[10] C.A. Baxter, E. Cleator, M.J. Karel, et al., The first large-scale synthesis of MK-4305: 273
a dual orexin receptor antagonist for the treatment of sleep disorder, Org. Process 274
Res. Dev. 15 (2011) 367–375.
275
[11] N.A. Strotman, C.A. Baxter, M.J. Karel, et al., Reaction development and mecha- 276
nistic study of a ruthenium catalyzed intramolecular asymmetric reductive 277
amination en route to the dual orexin inhibitor suvorexant (MK-4305), J. Am. 278
Chem. Soc. 133 (2011) 8362–8371.
[12] I.K. Mangion, B.D. Sherry, J.J. Yin, et al., Enantioselective synthesis of a dual orexin 280
receptor antagonist, Org. Lett. 14 (2012) 3458–3461.
[13] C.Q. Sun, W.R. Ewing, S.A. Bolton, et al., Substituted adipic acid amides and uses 282
thereof, WO2012125622.
279
281
283
[9] C.D. Cox, M.J. Breslin, D.B. Whitman, et al., Discovery of the dual orexin receptor
antagonist [(7R)-4-(5-chloro-1 3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-
Please cite this article in press as: Y. Chen, et al., Facile synthesis of suvorexant, an orexin receptor antagonist, via a chiral diazepane
intermediate, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.09.020