Enantioselective synthesis of a dual orexin receptor antagonist

Article abstract of DOI:10.1021/ol3014123

A concise, enantioselective synthesis of the potent dual orexin inhibitor suvorexant (1) is reported. Key features of the synthesis include a mild copper-catalyzed amination, a highly chemoselective conjugate addition, and a tandem enantioselective transamination/seven-membered ring annulation. The synthesis requires inexpensive starting materials and only four linear steps for completion.

Full text of DOI:10.1021/ol3014123

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3458–3461
Enantioselective Synthesis of a Dual
Orexin Receptor Antagonist
Ian K. Mangion,* Benjamin D. Sherry, Jingjun Yin, and Fred J. Fleitz
Department of Process Research, Merck and Co., Inc., P.O. Box 2000, Rahway, New
Jersey 07065, United States
ian_mangion@merck.com
Received May 22, 2012
ABSTRACT
A concise, enantioselective synthesis of the potent dual orexin inhibitor suvorexant (1) is reported. Key features of the synthesis include a mild
copper-catalyzed amination, a highly chemoselective conjugate addition, and a tandem enantioselective transamination/seven-membered ring
annulation. The synthesis requires inexpensive starting materials and only four linear steps for completion.
Orexins A and B are excitatory neuropeptides that stimu-
late wakefulness and play a central role in regulation of the
sleep cycle.1 Small molecule anta of orexin receptors OX1R
and OX2R2 have been found to promote sleep in multiple
species.3 Consequently, several laboratories have pursued the
design of selective orexin receptor antagonists for the treat-
ment of primary insomnia.4 Suvorexant (1) is a potent, brain-
penetrant dual orexin receptor antagonist recently disclosed
by Merck & Co. currently in phase III clinical trials.5 A
synthetic approach toward 1has been recently described,6 that
served as inspiration to design a novel approach that might
increase overall throughput with reduced cost and environ-
mental impact to satisfy projected commercial supply.
A key feature of 1 is the core chiral diazepane ring (2),
which had previously been assembled using a ruthenium-
catalyzed asymmetric reductive amination.7 This method
achieved high levels of enantioselectivity (94% ee) but
required the use of a transition metal catalyst and dichlor-
omethane as solvent, both of which we hoped to eliminate
to lessen the environmental impact of the process. There-
fore an alternative bond disconnection was envisioned
taking advantage of biocatalytic transamination technology
(Figure 1).8 Specifically, an asymmetric transamination of a
(1) For a review of studies on the orexin system, see: Hypocretins:
Integrators of Physiological Functions; de Lecea, L., Sutcliffe, J. G., Eds.;
Springer: New York, 2005.
(2) (a) De Lecea, L.; Kilduff, T. S.; Peyron, C.; Gao, X.-B.; Foye,
P. E.; Danielson, P. E.; Fukuhara, C.; Battenberg, E. L. F.; Gautvik,
V. T.; Bartlett, F. S., II; Frankel, W. N.; Van Den Pol, A. N.; Bloom,
F. E.; Gautvik, K. M.; Sutcliffe, J. G. Proc. Natl. Acad. Sci. U.S.A. 1998,
95, 322. (b) Sakurai, T.; Amemiya, A.; Ishii, M.; Matsuzaki, I.; Chemelli,
R.; Tanaka, H.; Williams, S. C.; Richardson, J. A.; Kozlowski, G. P.;
Wilson, S.; Arch, J. R. S.; Buckingham, R. E.; Haynes, A. C.; Carr, S. A.;
Annan, R. S.; McNulty, D. E.; Liu, W.; Terret, J. A.; Elshourbagy,
N. A.; Bergsma, D. J.; Yanagisawa, M. Cell 1998, 92, 573.
(3) (a) Boss, C.; Brisbare-Roch, C.; Jenck, F.; Aissaoui, H.; Koberstein,
R.; Sifferlen, T.; Weller, T. Chemia 2008, 62, 974. (b) Boss, C.;
Brisbare-Roch, C.; Jenck, F. J. Med. Chem. 2009, 52, 891.
(4) (a) McAtee, L. C.; Sutton, S. W.; Rudolph, D. A.; Li, X.; Aluisio,
L. E.; Phoung, V. K.; Dvorak, C. A.; Lovenberg, T. W.; Carruthers,
N. I.; Jones, T. K. Bioorg. Med. Chem. Lett. 2004, 14, 4225. (b) Bergman,
J. M.; Roecker, A. J.; Mercer, S. P.; Bednar, R. A.; Reiss, D. R.;
Ransom, R. W.; Harrell, C. M.; Pettibone, D. J.; Lemaire, W.; Murphy,
K. L.; Li, C.; Preuksaritanont, T.; Winrow, C. J.; Renger, J. J.; Koblan,
K. S.; Hartman, G. D.; Coleman, P. J. Bioorg. Med. Chem. Lett. 2008,
18, 1425. (c) Coleman, P. J.; Renger, J. J. Expert Opin. Ther. Patents
2010, 20, 307.
(6) Baxter, C. A.; Cleator, E.; Brands, K. M. J.; Edwards, J. S.;
Reamer, R. A.; Sheen, F. J.; Stewart, G. W.; Strotman, N. A.; Wallace,
D. J. Org. Process Res. Dev. 2011, 15, 367.
(7) Strotman, N. A.; Baxter, C. A.; Brands, K. M. J.; Cleator, E.;
Krska, S. W.; Reamer, R. A.; Wallace, D. J.; Wright, T. J. J. Am. Chem.
Soc. 2011, 133, 8362.
(8) For reviews on biocatalytic transformations, see: (a) De Wildeman,
S. M. A.; Sonke, T.; Schoemaker, H. E.; May, O. Acc. Chem. Res. 2007,
40, 1260. (b) Moore, J. C.; Pollard, D. J.; Kosjek, B.; Devine, P. N. Acc.
Chem. Res. 2007, 40, 1412. (c) Reetz, M. T. Angew. Chem., Int. Ed. 2011,
50, 138.
(5) Cox, C. D.; Breslin, M. J.; Whitman, D. B.; Schreier, J. D.;
McGaughey, G. B.; Bogusky, M. J.; Roecker, A. J.; Mercer, S. P.;
Bednar, R. A.; Lemaire, W.; Bruno, J. G.; Reiss, D. R.; Harrell, C. M.;
Murphy, K. L.; Garson, S. L.; Doran, S. M.; Prueksaritanont, T.;
Anderson, W. B.; Tang, C.; Roller, S.; Cabalu, T. D.; Cui, D.; Hartman,
G. D.; Young, S. D.; Koblan, K. S.; Winrow, C. J.; Renger, J. J.;
Coleman, P. J. J. Med. Chem. 2010, 53, 5320.
r
10.1021/ol3014123
Published on Web 06/22/2012
2012 American Chemical Society

ketone (4) that bears a suitable leaving group might allow for
a tandem transamination/medium ring annulation, complet-
ing the diazepane system. With reports of very highly
(>98% ee) enantioselective biocatalytic reactions and the
renewable nature of enzymatic catalysts it was proposed that
this approach might offer advantages in both reaction
performance and environmental sustainability. Further-
more, if the leaving group for the annulation could be
derived from activation of an alcohol, then compound 4
could be constructed from inexpensive starting materials
including ethanolamine (6, $6/kg) and methyl vinyl ketone
(7, $13/kg).
suitable leaving group. Investigations focused on an aza-
Michael addition of alcohol 11 to methyl vinyl ketone
(Table 1). The critical limitation of this reaction was found
to be achieving chemoselectivity between the amine and
alcohol functionalities, as each could react independently
providing ketones 12 and 13. Furthermore the reaction
was found to be thermodynamically driven to a mixture of
the two ketoneproductsalongwithsideproducts including
double alkylation, retro-Michael, and decomposition of
the hetreocycle.11 A careful survey of reaction conditions
was conducted, varying solvent and base composition to
improve chemoselectivity and yield.
Table 1. Optimization Studies for Aza-Michael Addition of 11
entrya
base
DBUd
solvent
yield (%)b
12:13c
1
CH3CN
CH3CN
CH3CN
CH3CN
THF
61
2
4:1
2
pyrrolidine
PPh3
1:1
Figure 1. Tandem transamination/ring annulation strategy.
3
7
3:1
4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
65
57
39
73
70
86
89
90
93
95
11:1
6:1
5
To investigate this synthetic strategy we first sought an
efficient synthesis of ketone 4 amenable to evaluation of a
number of possible leaving groups. First, an acid catalyzed
condensation of commercially available phenol 8 with tri-
methyl orthoformate provided benzoxazole 9 (Scheme 1).9
The reaction stream of 9 was then partially distilled to remove
methanol and then used directly in a subsequent lithiation/
bromination sequence to furnish bromide 10. This bromide
could then be reacted directly with ethanolamine in situ to
provide alcohol 11 without any intermediate chromatography
or isolation in 90% overall yield from 8.10
6
iPrOAc
DMF
13:1
16:1
14:1
21:1
32:1
30:1
37:1
42:1
7
8
DMAc
DMF
9
10
11
12
13
Na2CO3
Na3PO4
NaOH
NaOHe
DMF
DMF
DMF
DMF
a All reactions were conducted with 1.25 equiv of MVK and 5 mol %
base at 1 M solvent concentration and 23 °C under nitrogen unless
otherwise noted. b Isolated yield of 12. c Ratio determined by HPLC.
d 1,8-Diazabicyclo[5.4.0]undec-7-ene. e Run with 1 mol % 10 M NaOH.
DBU was found to be sufficiently basic to promote the
aza-Michael reaction, but yield and selectivity were mod-
erate (Table 1, entry 1). A range of less basic tertiary
Scheme 1. One-Pot Synthesis of Alcohol 11
(9) For related heterocyclic condensations, see: (a) Vechorkin, O.;
Hirt, N.; Hu, X. Org. Lett. 2010, 12, 3567. (b) Cioffi, C. L.; Lansing, J. J.;
€
Yuksel, H. J. Org. Chem. 2010, 75, 7942.
(10) The synthesis of aminobenzoxazoles from benzoxazoles has also
been reported via direct oxidative methods; see: (a) Guo, S.; Qian, B.;
Xie, Y.; Xia, C.; Huang, H. Org. Lett. 2011, 13, 522. (b) Froehr, T.;
Sindlinger, C. P.; Kloeckner, U.; Finkbeiner, P.; Nachtsheim, B. J. Org.
Lett. 2011, 13, 3754. (c) Wertz, S.; Kodama, S.; Studer, A. Angew. Chem.
Int. Ed.. 2011, 50, 11511. (d) Li, Y.; Xie, Y.; Zhang, R.; Jin, K.; Wang, X.;
Duan, C. J. Org. Chem. 2011, 76, 5444. (e) Lamani, M.; Prabhu, K. R.
J. Org. Chem. 2011, 76, 7938.
(11) This decomposition largely consisted of opening of the oxazole
by addition of ethanolamine to the C2 position. For related reactions,
see: (a) LaMattina, J. L.; Mularski, C. J. Tetrahedron Lett. 1984, 25,
2957. (b) Walker, F. J.; Kraus, K. G. J. Heterocycl. Chem. 1987, 24,
1585. (c) Kokel, B. 1996, 37, 3849.
To access the proposed transamination substrate (4) it
remained to append a ketone and activate the alcohol as a
Org. Lett., Vol. 14, No. 13, 2012
3459

amines failed to promote reactivity, although slight reac-
tivity was seen with pyrrolidine or triphenylphosphine
(entries 2ꢀ3). Higher yields and selectivities were observed
with inorganic bases (entries 4ꢀ13). A solvent survey with
cesium carbonate revealed DMF to be a preferable solvent
with 73% yield and 16:1 chemoselectivity (entry 7). To our
delight, a range of alkali carbonates and phosphates
mediated the reaction with excellent yields and selectivities
(entries 9ꢀ11). However, occasional reproducibility pro-
blems were observed on increasing reaction scale because
of the limited solubility of the inorganic salts. It was
realized that the active catalyst was likely trace hydroxide
from adventitious water. Therefore aqueous sodium hy-
droxide was evaluated as a catalyst and found to promote
theconjugate addition in95% yield and 42:1selectivityasa
1 mol % additive (entry 13). These conditions were then
applied to a one-step synthesis of mesylate 14 from alcohol
11, following the aza-Michael with mesylation and crystal-
lization of the product in 81% yield (eq 1).
Figure 2. Side reactions competing with annulation step.
Furthermore, the desired tandem annulation to 2 was
observed during the reaction. However, signficant
amounts of side products 15 and 17 were observed, and
yield was also impacted by hydrolysis of the sulfonate
activating group. A range of sulfonates were examined
under identical conditions (entries 2ꢀ5), but mesylate 14
was ultimately superior in overall profile. The tosylate
provided better selectivity against formation of guanidine
15 (entry 2), but slower reaction kinetics and poorer
sulfonate stability resulted in a diminished yield, likely
because of its reduced solubility in the mixed aqueous
reaction medium. Interestingly, an alkyl chloride provided
clean reactivity in the transamination (entry 6) but only
15 was observed as a product because the chloride was
apparently insufficiently reactive to compete with the
benzoxazole ring-opening pathway. By rendering the pH
of the reaction more basic (entries 7ꢀ10), formation of 15
and 17couldbereduced. However, atapHof 10orgreater,
yield was diminished because of sulfonate and enzyme
instability (entries 9ꢀ10). Using a moderate pH and a slow
addition protocol for 14 provided a useful balance between
the reactivity and purity profile (entry 11, 71% yield).16
Notably, in all cases shown here enantioselectivity was
greater than 99%.
With mesylate 14 in hand, the stage was set to evaluate
the crucial transamination sequence. However, a highly
selective transamination of the ketone (4 to 3, Figure 2) is
only one of several possible issues anticipated in the
proposed tandem reaction. The benzoxazole had proven
earlier to be labile to nucleophilic attack, and the transa-
mination event might initiate an intramolecular ring
opening (4 to 15). Also, the desired amine (2) had been
previously reported to be capable of isomerization (2 to
17),6 which in our studies occurred in a pH range of 3 to
12.12 The leaving group (X) could be susceptible to hydro-
lysis under basic reaction conditions; however basic con-
ditions would be required for the annulation step to
proceed. A high-yielding process would have to balance
these competing factors successfully.
Several (R)-selective transaminases are commercially
available,13 but an initial survey found many to be insuffi-
ciently reactive to achieve significant conversion.14 How-
ever, the (R)-selective transaminase evolved specifically for
the sitagliptin manufacturing process15 provided good
conversion and exceptionally high enantioselectivty in
the transamination of 14 (Table 2, entry 1, >99% ee).
With a method in hand to produce 2, it remained to
complete the synthesis of 1 by amide formation with
(12) Below pH 3 amine 2 is predominantly doubly protonated, and
above pH 12 it is free based. High or low pH regimes suppress
intermediate 16, which arises from a singly protonated species, and
therefore isomerization is also suppressed.
(13) For synthetic applications of (R)-selective transaminases, see:
(a) Truppo, M. D.; Turner, N. J.; Rozzell, D. Chem. Commun. 2009,
2127. (b) Koszelewski, D.; Clay, D.; Rozzell, D.; Kroutil, W. Eur. J. Org.
Chem. 2009, 2289. (c) Koszelewski, D.; Tauber, K.; Faber, K.; Kroutil,
W. Trends Biotechnol. 2010, 28, 324.
(14) An unoptimized lead of 8% yield was found using ATA-117
(Codexis) as the transaminase.
(15) This is an evolved variant of ATA-117; see round 11 transami-
nase in: Savile, C. K.; Janey, J. M.; Mundorff, E. C.; Moore, J. C.; Tam,
S.; Jarvis, W. R.; Colbeck, J. C.; Krebber, A.; Fleitz, F. J.; Brands, J.;
Devine, P. N.; Huisman, G. W.; Hughes, G. J. Science 2010, 329, 305.
triazole acid 19. This acid was synthesized via an Ullman-
type copper catalyzed amination of 1,2,3-triazole which
had initially suffered from moderate regioselectivity.6
3460
Org. Lett., Vol. 14, No. 13, 2012

Table 2. Tandem Transamination/Annulation Optimization
Scheme 2
entrya
pH
X
yield (%)b
15 (%)b
17 (%)b
1
8.5
8.5
8.5
8.5
8.5
8.5
9.0
9.5
10.0
11.0
9.5
OMs
OTs
60
45
38
10
17
0
10
3
12
9
6
3
4
0
9
4
3
1
2
2
3
OSO2(4-FPh)
OSO2CH2Cl
ONsc
4
4
2
5
3
6
Cl
92
9
7
OMs
63
65
58
8
suvorexant (1) in a volume efficient process in 96% yield
after crystallization (Scheme 2).
8
OMs
8
9
OMs
4
In conclusion, a concise, enantioselective synthesis of
suvorexant, a potent and selective dual orexin receptor
antagonist for the treatment of primary insomnia, has been
developed. This approach features an unusual tandem
transamination/medium ring annulation to produce the
core diazepane that proceeds in greater than 99% ee.
The entire synthesis requires only four linear steps for
completion and proceeds in 43% overall yield without
the need for chromatography. Use of halogenated
solvents or heavy metal catalysts has been eliminated,
rendering this synthesis attractive for a more sustainable
large scale commercial supply.
10
11d
OMs
1
OMs
71
6
a All reactions were conducted at 40 °C with 20 wt % CDX-017, 0.5
wt % pyridoxal 50-phosphate, and 6 equiv of iPrNH2 HCl in a DMSO/
3
water solution buffered to target pH by triethanolamine. b Assay yield
determined by HPLC. c p-Nitrobenzenesulfonate. d 14 added via syringe
pump over 6 h as DMSO solution.
Interestingly, improved regioselectivity was observed at
rt in the absence of an exogenous ligand (eq 2, 88:12
19:20).17 Regioisomerically pure 19 could then be ob-
tained in 70% yield through crystallization.19
Following workup of the transamination, amine 2 was
crystallized directly as its HCl salt (21) and coupled with
acid19under SchottenꢀBaumann conditions19 toproduce
Acknowledgment. The authors would like to thank Dr.
Debra J. Wallace (Merck) for helpful discussions.
(16) The mass balance consists of 12 from hydrolysis of the sulfonate
and oligomers dervied from intermolecular alkylation of amine 3.
(17) For examples of rt Ullman-type couplings, see: (a) Ley, S. V.;
Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (b) Shafir, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742.
(18) For Pd-catalyzed regioselective CꢀN couplings of triazoles, see:
Ueda, S.; Su, M.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 8944.
(19) Sonntag, N. O. V. Chem. Rev. 1952, 52, 237.
Supporting Information Available. Experimental pro-
1
ceudres, compound characterization, and copies of H
and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
3461