Identification, synthesis and strategy for minimization of potential impurities in the synthesis of suvorexant

Article abstract of DOI:10.1080/00397911.2021.1930055

Eight process-related impurities in the synthesis of suvorexant were identified, while six of them were described for the first time. In order to get the references for the process optimization and quality control of API, the eight compounds were synthesized. According to the possible formation pathways, a modified synthesis and the strategy for impurity control in the corresponding reactions were established.

Full text of DOI:10.1080/00397911.2021.1930055

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Identification, synthesis and strategy for
minimization of potential impurities in the
synthesis of suvorexant
Xunlei Lv, Jing Pan, Weiyuan Liu, Xue Meng, Liang Chen, Ting Zhou, Kuaile
Lin, Deyong Ye & Weicheng Zhou
To cite this article: Xunlei Lv, Jing Pan, Weiyuan Liu, Xue Meng, Liang Chen, Ting Zhou, Kuaile
Lin, Deyong Ye & Weicheng Zhou (2021) Identification, synthesis and strategy for minimization of
potential impurities in the synthesis of suvorexant, Synthetic Communications, 51:14, 2225-2236,
DOI: 10.1080/00397911.2021.1930055
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2021, VOL. 51, NO. 14, 2225–2236
https://doi.org/10.1080/00397911.2021.1930055
Identification, synthesis and strategy for minimization of
potential impurities in the synthesis of suvorexant
a,b
b
b
b
b
Xunlei Lva,b , Jing Pan
, Weiyuan Liu , Xue Meng , Liang Chen , Ting Zhou ,
ꢀ
ꢀ
Kuaile Linb, Deyong Yea, and Weicheng Zhoub
b
aSchool of Pharmacy, Fudan University, Shanghai, China; State Key Laboratory of New Drug and
Pharmaceutical Process, Shanghai Key Laboratory of Anti-infectives, State Institute of Pharmaceutical
Industry, Shanghai, China
ABSTRACT
ARTICLE HISTORY
Received 10 March 2021
Eight process-related impurities in the synthesis of suvorexant were
identified, while six of them were described for the first time. In
order to get the references for the process optimization and quality
control of API, the eight compounds were synthesized. According to
the possible formation pathways, a modified synthesis and the strat-
egy for impurity control in the corresponding reactions were estab-
lished.
KEYWORDS
Impurities; suvorexant;
synthesis
GRAPHICAL ABSTRACT
Introduction
Suvorexant (1, Scheme 1), a dual orexin receptor (OX1R and OX2R) antagonist, was
approved in 2014 by FDA for the clinical treatment of insomnia characterized by diffi-
culty achieving and/or maintaining sleep.[1] At present, the main method to produce
suvorexant was chemical synthesis.
The presence of impurities (also called the related substances) in an active pharma-
ceutical ingredient (API) can influence significantly the safety and efficacy of the drug
CONTACT Deyong Ye
Pudong New District, Shanghai 201203, China; Weicheng Zhou
dyye@shmu.edu.cn
School of Pharmacy, Fudan University, No. 826, Zhangheng Rd.,
zhouweicheng58@163.com State Key Laboratory
of New Drug and Pharmaceutical Process, Shanghai Key Laboratory of Anti-infectives, State Institute of Pharmaceutical
Industry, No. 285, Gebaini Rd., Pudong New District, Shanghai 201203, China.
ꢀ
Contributed equally to this work.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2021 Taylor & Francis Group, LLC

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X. LV ET AL.
Scheme 1. Synthesis of suvorexant 1.
substance. So, the research on the impurity profile which is the basis of specification
setting for API is of great significance. Meanwhile, identification of the impurities or
the by-products can help the organic chemists to understand the reactions better in
order to optimize the process. Although there are many publications on the synthesis of
suvorexant,[2–9] to the best of our knowledge, no systematic study of the impurity
profile of suvorexant has been reported.
In this context, the identification and synthesis of eight observed or potential impur-
ities of suvorexant were presented. Among them, compound B, D, E, F, G and H were
reported for the first time and two (A and C) appeared in the literatures.[7,10] At the
same time, according to the possible formation pathways of impurities, an improved
synthesis and the strategy for minimization of the impurities were established.
Results and discussion
Various synthetic methods were available in literatures[2–8] for the preparation of 1. The
route in Scheme 1 was regarded as the process synthesis. It involves the following steps:
the nucleophilic substitution of 2,5-dichlorobenzoxazole (2) with Boc-protected ethylene-
diamine to give (2-((5-chloro-1,3-benzoxazol-2-yl)amino)ethyl)carbamic tert-butyl ester
(3), alkylation of 3 with 4-tosyloxy-2-butanone (5), deprotection of (2-((5-chlorobenzoxa-
zol-2-yl)-(3-oxo-butyl)-amino)ethyl)carbamic tert-butyl ester (6) with methanesulfonic
acid (MSA), asymmetric reductive amination of 4-((2-amino-ethyl)-(5-chlorobenzoxazol-
2-yl)amino)butan-2-one-bis-MSA Salt (7), and acylation of (R)-5-chloro-2-(5-methyl-
[1,4]diazepan-1-yl)-benzoxazole (8) with 5-methyl-2-[1,2,3]triazol-2-yl-benzoyl chloride
(9) to afford suvorexant (1).
The crude product was obtained by the above route and two trace impurities were
detected by HPLC (Figure 1) and HPLC-MS showed that they both had the same
molecular weight as compound 1. It was reported that compound 8 could undergo an
intramolecular ring flip to form 8a and then coupled with 9 to give impurity A[7,8]
(Scheme 2). Another impurity (called as impurity B) might be referred to the preparation
of 5-methyl-2-[1,2,3]triazol-2-yl-benzoic acid (10) where the regio-isomer 5-methyl-2-
[1,2,3]triazol-1-yl-benzoic acid (11) might be the by-product. If trace of 11 in compound
10 underwent the same reactions, impurity B was formed (Scheme 3). In order to con-
firm the above inference, compound A and B were synthesized respectively (Scheme 4).

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Figure 1. HPLC chromatogram of crude 1.
Scheme 2. Proposed pathway to impurity A.
Scheme 3. Proposed pathway to impurity B.
1-tert-butoxycarbonyl-7-methyl-1,4-diazabicycloheptane (A-1) reacted with compound 9
to give 1-tert-butoxycarbonyl-4-(5-methyl-2-[1,2,3]triazol-2-yl-benzoyl)-7-methyl-1,4-dia-
zabicycloheptane (A-2), after deprotection of A-2, 4-(5-methyl-2-[1,2,3]triazol-2-yl-ben-
zoyl) ꢁ7-methyl-1,4-diazabicycloheptane (A-3) reacted with 2 to give compound A
(Scheme 4).Then, with the identified synthetic compounds A and B as the references, the
HPLC proved that the impurity at RT (retention time) of 38.073 min was compound A
and that at RT of 16.750 min was compound B (Figure 1, RT of compound
1: 35.993 min).
There is a chiral carbon atom in 1 and the R-isomer is used as the API. According to
the International Council for Harmonization of Technical Requirements for

2228
X. LV ET AL.
Scheme 4. Synthesis of A–H.
Pharmaceuticals (ICH), control of the content of the corresponding enantiomer
(S-isomer, called impurity C) was necessary in order to secure the safety and efficacy of
the drug. Impurity C may come from the asymmetric reductive amination. In order to
get (S)-8 and compound C, (rac)-8 was subjected to resolution with dibenzoyl-L-tartaric
acid (L-DBT) to give the desired (S)-8, further reaction with 9 afforded compound C
(Scheme 4). Subsequently, a chiral HPLC method was established to separate suvorexant
and impurity C or (R)-8 and (S)-8, as showed in Figures 2 and 3.
It is important to control the quality of compound 8 because it could result in the
formation of both impurity A and C. The salt formation of the crude 8 with dibenzoyl-

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2229
Figure 2. Chiral HPLC chromatogram of suvorexant and impurity C.
Figure 3. Chiral HPLC chromatogram of (R)-8 and (S)-8.
D-tartaric acid (D-DBT) in isopropyl acetate (IPA) followed by washing with
IPA þ MeOH was an effective way to purify compound 8. The asymmetric reductive
amination gave compound 8 with a chiral purity of 96.94%, after these operations, the
chiral purity was improved to 99.47% and the achiral purity reached 100%. Meanwhile,
in order to monitor the competitive reduction of the ketone in the synthesis of com-
pound 8, the potential impurity H was also synthesized from compound 6 via reduction
and deprotection (Scheme 4). The analysis of compound 8 also showed that it was con-
taminated with about 0.02% of impurity H, which could be eliminated by above
salt formation.
As far as impurity B was concerned, the tests showed that if the content of com-
pound 11 in product 10 was controlled under a reasonable level (less than 0.5%),

2230
X. LV ET AL.
Scheme 5. Proposed pathway to impurity D.
Scheme 6. Proposed pathway to impurity E.
impurity B in API could be minimized (below 0.1%) or eliminated. In the end,
suvorexant was obtained with an achiral purity of 100% and a chiral purity
of 99.93%.
In the beginning, compound 3 was prepared by substitution between 2 and Boc-pro-
tected ethylenediamine in dichloromethane with triethylamine as a base, according to
the literature.[7] Although the reaction went quite well, two impurities were separated
from crude 3, and the structures were identified as compound D and compound E by
1
MS and H NMR (Scheme 4). The diethylamino fragment in D should come from the
reaction of 2 with triethylamine via SNAr mechanism, as reported in the similar litera-
ture[11] (Scheme 5). For the preparation, compound D was obtained from the reaction
of compound 2 with diethylamine (Scheme 4). It seems that compound E was caused
by the overreaction of product 3 with 2 (Scheme 6). In practice, compound E was syn-
thesized from compound 3 and 2 in THF with Na2CO3 as a base (Scheme 4).
In order to eliminate impurity D, the reaction of 2 with Boc-protected ethylenedi-
amine was carried out in heterogeneous system (toluene/H2O) with NaOH as base.
Although impurity E was detected in the reaction mixture, it could be removed by
workup (filtration) and compound 3 was obtained with a yield of 95% and a purity
of 99.98%.
When compound 6 was prepared by alkylation of 3 with 5, an impurity (called
impurity F) with the same molecular weight as compound E was separated. Compared
with compound E, besides the different behave in HPLC, impurity F showed two sets of
1
benzoxazole H NMR signals, so its structure was identified. The formation pathway
was proposed in Scheme 7. For preparation, compound F was obtained also by the con-
densation of 2 and 3, but the reaction went under much more rigorous condition than
the preparation of compound E, shown in Scheme 4.
It seems that both E and F are related to the preparation of compounds 3 and 6, so
the crude of both 3 and 6 was reexamined by HPLC with E and F as the references.

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Scheme 7. Proposed pathway to impurity F.
About 0.07% of E was determined with no detection of F in the crude of 3, meanwhile,
in the crude of 6, the content of F was 0.10%, but no track of E was found.
During the synthesis of compound 7, another trace impurity was observed, which
1
was identified as compound G by MS and H NMR. Obviously, it was caused by trace
residue of 3 in compound 6 (Scheme 4).
Both impurity F and G can be completely removed by recrystallization of compound
6 with iPrOH: heptane (8:2).
Conclusion
In summary, eight impurities in the synthetic process of suvorexant have been identified
and these compounds were synthesized as the references for both the process modifica-
tion and the quality control on API. Among them, six compounds have not been found
in the literature before. The possible formation pathways were discussed and the strat-
egy for minimization or elimination of impurities has also been demonstrated in the
synthetic process of suvorexant.
Experimental section
General methods
Solvents and reagents from commercial were used as received unless otherwise indicated.
NMR spectra were measured on a Bruker Avance III 400 or 600 MHz spectrometer with
TMS as an internal standard. Mass spectra were recorded with a Q-TOF mass spectrometer
using electrospray positive ionization (ESIþ). The HRMS data were obtained using Q-TOF
€
micro mass spectrometry. Melting points were determined on a Buchi melting point M-565
apparatus. Optical rotation was recorded on a Rudolph Autopol IV polarimeter. The angle
of rotation was recorded at 20ꢂC on 1% solutions in MeOH. Column chromatography was
carried out on silica gel (HF254) purchased from Qingdao Ocean Chemical Company of
China. HPLC Method in Figure 1: Agilent Extend C18 column (4.6 mm ꢃ 250 mm, 5 lm)
with mobile phase A: tetrabutylammonium bisulfate aqueous solution; mobile phase B:
acetonitrile; Column temperature: 40ꢂC; flow rate: 1.0 mL/min. Gradient (A: B ¼ 58:42, v/
v). HPLC Method in Figure 2: Chiralpak IA column (4.6 mm ꢃ 250 mm, 5 lm) with mobile
phase A: hexane (75); mobile phase B: isopropanol (25); Column temperature: 40ꢂC; flow
rate: 1.0 mL/min. Gradient (A: B ¼ 75:25, v/v). HPLC Method in Figure 3: Chiralpak AD-H
column (4.6 mm ꢃ 250 mm, 5 lm) with mobile phase A: hexane; mobile phase B: 0.1%

2232
X. LV ET AL.
diethylamine ethanol solution; Column temperature: 35ꢂC; flow rate: 0.6 mL/min. Gradient
(A:B ¼ 60:40, v/v).
(4-(5-Chlorobenzoxazol-2-yl)-5-methyl- [1,4] diazepan-1-yl)-(5-methyl-2-[1,2,3] triazol-
2-yl-phenyl)methanone (compound A)
Compound 9 (3.25 g, 14.67 mmol) was dissolved in DCM (25 mL) and cooled to
0–10 ꢂC. Then the solution of A-1[8] (2.86 g, 13.36 mmol) in 20 ml DCM and Et3N
(1.53 g, 15.14 mmol) were added drop-wise and the resulting mixture stirred for 3 h.
The reaction mixture was poured into water (50 mL). The organic phase was separated
and the aqueous layer was extracted with DCM (2 ꢃ 25 mL). The organic extracts were
combined and washed with water (3 ꢃ 100 mL), dried over anhydrous Na2SO4, filtered
and evaporated under reduced pressure to obtain the crude product, which was purified
by column chromatography (1:5 EtOAc/petroleum) to yield A-2 (3.20 g, 60%).
Compound A-2 (2.00 g) were stirred in HCl (2 M in MeOH) (50 mL) for 4 h at room
temperature. The reaction mixture was poured into DCM (100 mL) and the pH of the
solution was adjusted to 9 with NaOH aq. (2 mol/L). The organic phase was separated
and the aqueous layer was extracted with DCM (2 ꢃ 50 mL). The organic extracts were
combined and washed with water, dried over anhydrous Na2SO4, filtered and evapo-
rated under reduced pressure to afford A-3 (1.2 g, 81%). Compound A-3 (0.80 g,
2.66 mmol), compound 2 (0.50 g, 2.66 mol), and Et3N (0.30 g, 2.97 mmol) were dissolved
in DMF (10 mL) and stirred for 4 h at room temperature. The reaction mixture was
poured into water (50 mL). The mixture was then extracted with DCM (3 ꢃ 50 mL) and
the combined organic extracts were washed with water, dried over anhydrous Na2SO4,
filtered and evaporated under reduced pressure to yield the crude product which was
purified by column chromatography (70:1 DCM/MeOH) to give a white solid. Yield:
1
80% (0.96 g); HPLC: 99.79%. Mp:172–174 ꢂC. H NMR (600 MHz, CDCl3) d: 7.91–7.61
(m, 3H), 7.33–7.24 (m, 2H), 7.19–7.06 (m, 2H), 6.99–6.92 (m, 1H), 4.81–4.02 (m, 2H),
4.23–3.81(m, 1H), 3.70–3.46 (m, 1H), 3.44–3.11 (m, 2H), 3.07–2.82 (m, 1H), 2.43–2.31
(m, 3H), 2.03–1.61 (m, 2H), 1.36–1.16 (m, 3H). 13C NMR (150 MHz, CDCl3) d 169.28,
169.08, 169.05, 168.77, 162.89, 162.79, 162.65, 147.44, 147.41, 147.34, 144.72, 144.61,
138.66, 138.52, 135.75, 135.62, 135.58, 134.23, 133.84, 130.70, 130.63, 130.56, 129.39,
129.34, 129.31, 128.92, 128.89, 128.70, 128.45, 128.30, 128.09, 122.60, 122.44, 122.15,
122.03, 120.30, 120.21, 116.21, 109.31, 109.17, 64.33, 52.78, 52.72, 52.64, 49.97, 49.38,
46.56, 46.36, 45.11, 44.06, 43.98,43.62, 43.40, 41.88, 41.16, 35.81, 35.02, 34.43, 34.36,
25.40, 21.07, 21.02, 20.94, 19.35, 19.02, 18.86. HRMS (ESI): m/z calcd. for
C23H23ClN6O2 [M þ H]þ: 451.1644, found 451.1643.
((R)-4-(5-chlorobenzoxazol-2-yl)-7-methyl-[1,4]diazepan-1-yl)-(5-methyl-2-[1,2,3] tria-
zol-1-yl-phenyl)methanone (compound B)
Compound 11a (1.63 g, 7.38 mmol) was dissolved in DCM (25 mL) and cooled to
0–10 ꢂC. Then the solution of (R)-8 (2.15 g, 8.12 mmol) in 20 ml DCM and Et3N (0.89 g,
8.81 mmol) were added drop-wise and the resulting mixture stirred for 1 h. The reaction
mixture was poured into water (50 mL). The organic phase was separated and the aque-
ous layer was extracted with DCM (2 ꢃ 25 mL). The organic extracts were combined

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2233
and washed with water, dried over anhydrous Na2SO4, filtered and evaporated under
reduced pressure to obtain the crude product which was purified by column chromatog-
raphy (2:1 EtOAc/petroleum) to afford a white solid. Yield:69% (2.3 g); HPLC: 99.20%.
Mp: 86–89 ꢂC. [a]20 ¼ ꢁ14.94 (c 1.00, MeOH); 1H NMR (600 MHz, CDCl3)
D
d: 8.04–7.90 (m, 1H), 7.80–7.71 (m, 1H), 7.59–7.44 (m, 1H), 7.40–7.37 (m, 1H),
7.31–7.17 (m, 2H), 7.15–7.05 (m, 1H), 6.98–6.93 (m, 1H), 4.44–4.19 (m, 1H), 4.05–3.93
(m, 1H), 3.85–3.73 (m, 1H), 3.56–3.38 (m, 1H), 3.20–3.07 (m, 1H), 3.03–2.66 (m, 1H),
2.47–2.40 (m, 3H), 2.27–1.99 (m, 2H), 1.74 ꢁ 1.49 (m, 1H), 1.18–0.62 (m, 3H); 13C
NMR (150 MHz, CDCl3) d 168.07, 167.89, 167.75, 162.30, 162.23, 162.16, 147.04,
147.00, 144.18, 144.01, 140.19, 139.87, 139.79, 133.61, 133.51, 133.68, 132.07, 131.71,
130.65, 130.53, 130.41, 128.95, 128.82, 127.40, 127.17, 126.90, 125.27, 125.03, 124.92,
124.88, 124.77, 124.56, 120.05, 119.86, 115.88, 115.74, 108.91, 108.82, 108.77, 72.35,
52.13, 51.53, 48.98, 48.40, 47.80, 47.28, 46.42, 45.78, 44.70,43.81, 43.65, 40.91, 39.31,
35.68, 34.67, 33.14, 32.78, 30.76, 26.51, 24.89, 20.77, 19.71, 17.82, 17.30, 16.85. HRMS
(ESI): m/z calcd. for C23H23ClN6O2 [M þ H]þ: 451.1644, found 451.1646.
((S)-4-(5-chlorobenzoxazol-2-yl)-7-methyl-[1,4]diazepan-1-yl)-(5-methyl-2-[1,2,3] tria-
zol-2-yl-phenyl)methanone (compound C)
NaBH4 (2.40 g, 63.35 mmol) was added into acetic acid (25.30 g, 422.38 mmol) and
stirred for 10 min at room temperature. DCM (200 mL) and sodium acetate (3.46 g,
42.23 mmol) were then added and stirred at 0–10 ꢂC for 10 min. Compound 7 (20.00 g,
42.23 mmol) was then added and the resulting mixture stirred for 1.5 h. HCl aq.
(2 mol/L) (50 mL) was then added to quench the reaction and the pH of the solution
was adjusted to 9 with NaOH aq. (5 mol/L). The organic phase was separated and the
aqueous layer was extracted with DCM (2 ꢃ 100 mL). The organic extracts were com-
bined and washed with water, dried over anhydrous Na2SO4, filtered and evaporated
under reduced pressure to obtain (rac)-8 (10.5 g, 93.66%). Dibenzoyl-L-tartaric acid
(33.7 g, 94.13 mmol) was dissolved in THF (40 mL) and the solution cooled to 10 ꢂC.
Compound (rac)-8 (10 g, 37.66 mmol) (dissolved in DCM (10 mL)/THF (60 mL)) was
added drop-wise to the solution and left to stirred for 5 h at 20 ꢂC. The slurry was fil-
tered and the solid washed with THF (3 ꢃ 10 mL) to give a white solid 10.50 g. The
L-DBT salt 8 (10 g, 16.03 mmol), iPAc (80 mL) and MeOH (30 mL) were added to a
250 ml round bottomed flask. The slurry stirred for 20 h at room temperature and fil-
tered to give a white solid 6.70 g. The L-DBT salt 8 (5.20 g) was treat with NaOH aq.
(4 mol/L) in DCM to give (s)-8, 2.20 g. Compound 9 (1.83 g, 8.28 mmol) was dissolved
in DCM (25 mL) and cooled to 0–10 ꢂC. Then the solution of (s)-8 (2.00 g, 7.53 mmol）
in DCM (20 mL) and Et3N (0.91 g, 9.01 mmol) were added drop-wise and the resulting
mixture stirred for 1 h. The reaction mixture was poured into water (50 mL). The
organic phase was separated and the aqueous layer was extracted with DCM
(2 ꢃ 25 mL). The organic extracts were combined and washed with water, dried over
anhydrous Na2SO4, filtered and evaporated under reduced pressure to obtain the crude
product which was purified by recrystallization from acetonitrile/water (1:1) to give a
white solid. Yield: 82% (2.78 g). HPLC: 98.25%, chiral HPLC: 98.69%. Mp:132–134 ꢂC;
[a]20 ¼ þ11.21 (c 1.00, MeOH)； 1H-NMR and 13C-NMR and melting point data
D
were in accordance with published patents.[5,6,10] 1H NMR (600 MHz, CDCl3)

2234
X. LV ET AL.
d: 7.96–7.89 (m, 1H), 7.82–7.69 (m, 2H), 7.36–7.27 (m, 2H), 7.22–7.05 (m, 2H),
7.01–6.98 (m, 1H), 7.15–7.05 (m, 1H), 6.98–6.93 (m, 1H), 5.05–4.57 (m, 1H), 4.25–4.03
(m, 2H), 3.93–3.83 (m, 1H), 3.77–3.39 (m, 2H), 3.24–3.07 (m, 1H), 2.44–2.34 (m, 3H),
2.14–1.85 (m, 1H), 1.82–1.54 (m, 1H), 1.32–1.16 (3H, m), 1.00–1.18 (3H, m); 13C NMR
(150 MHz, CDCl3) d 169.91, 169.43, 169.40, 169.27, 163.04, 162.90, 162.75, 162.68,
147.49, 147.47, 147.42, 144.73, 144.62, 144.60, 144.54, 138.59, 138.56, 138.44, 138.19,
135.67, 135.60, 135.55, 135.46, 134.03, 133.92, 133.60, 133.56, 130.59, 129.41, 129.37,
128.92, 128.80, 128.69, 128.48, 128.40, 128.27, 122.54, 122.20, 122.11, 120.44, 120.38,
120.31, 116.33, 116.21, 109.32, 109.22, 109.12, 52.21, 51.51, 48.88, 48.36, 48.10, 47.62,
47.28, 47.05, 45.57,45.13, 44.90, 44.39, 44.05, 43.83, 41.02, 39.92, 36.26, 35.48, 34.23,
33.90, 21.02, 21.00, 20.96, 20.94, 19.90, 17.91, 17.81, 16.69. HRMS (ESI): m/z calcd. for
C23H23ClN6O2 [M þ H]þ: 451.1644, found 451.1646.
2-Diethylamino-5-chlorobenzoxazol (compound D). Compound 2 (5.00 g, 26.6 mmol) was
dissolved in THF (25 mL) and the solution cooled to 0–10 ꢂC. Diethylamine (5.83 g,
79.86 mmol) was then added drop-wise and the resulting mixture stirred for 1 h at
room temperature. The reaction mixture was poured into water (50 mL). The mixture
was then extracted with ethyl acetate (3 ꢃ 50 mL) and the organic extracts were com-
bined and washed with water, dried over anhydrous Na2SO4, filtered and evaporated
under reduced pressure to give the crude. The crude product was recrystallized
from isopropanol (19 ml) to give a yellow solid. Yield: 39% (2.32 g); HPLC:
99.16%. Mp:42–45 ꢂC.1H NMR (600 MHz, CDCl3) d 7.22 (d, J ¼ 3 Hz, 1H,), 7.05
(d, J ¼ 12.6 Hz, 1H), 6.86 (dd, J ¼ 12.6 Hz, 3.6 Hz, 1H), 3.46–3.52 (m, 4H), 1.20
(t, J ¼ 10.8 Hz, 1H); 13C NMR (150 MHz, CDCl3) d 161.94, 146.43, 144.05, 128.03,
118.64, 114.81, 107.91, 42.01, 12.40. HRMS (ESI): m/z calcd. for C11H13ClN2O
[M þ H]þ: 225.0789, found 225.0793.
(2-(Bis(5-chlorobenzoxazol-2-yl)amino)ethyl)carbamic acid tert-butyl ester (compound
E)
Compound 3 (2.00 g, 6.42 mmol) and compound 2 (2.00 g, 10.63 mmol) were dissolved
in THF (30 mL). Saturated Na2CO3 aq. (16 mL) was then added and the solution was
allowed to warm to 50 ꢂC for 36 h. The reaction was cooled to room temperature.
The mixture was then extracted with ethyl acetate (3 ꢃ 50 mL) and the organic extracts
were combined and washed with brine, dried over anhydrous Na2SO4, filtered and
evaporated under reduced pressure to give the crude which was purified by column
chromatography (10:1 DCM/MeOH) give
a
white solid. Yield:15% (0.48 g);
1
HPLC: 98.45%. Mp: 167–170 ꢂC. H NMR (600 MHz, CDCl3) d 7.58 (d, J ¼ 2.4 Hz, 2H),
7.42 (d, J ¼ 8.4 Hz, 2H), 7.24 (dd, J ¼ 8.4 Hz, 2.4 Hz, 2H), 5.10 (br, 1H), 4.53–4.55
(t, J ¼ 5.4 Hz, 2H), 3.67–3.68 (m, 2H) 1.30 (s, 9H); 13C NMR (150 MHz, CDCl3)
d 157.41, 155.94, 147.63, 142.12, 130.31, 123.76, 118.73, 110.84, 79.52, 50.20, 39.14,
28.23. HRMS (ESI): m/z calcd. for C21H20Cl2N4O4 [M þ Na]þ: 485.0754,
found 485.0755.

R
SYNTHETIC COMMUNICATIONSV
2235
(5-Chlorobenzo[d]oxazol-2-yl)(2-((5-chlorobenzoxazol-2-yl)amino)ethyl)carbamic acid
tert-butyl ester (compound F)
Compound 3 (5.00 g, 16.05 mmol) was dissolved in THF (50 mL) and the solution
cooled to 5 ꢂC. Then NaH (60%) (0.71 g, 17.65 mmol) was then added and the resulting
mixture stirred for 0.5 h at 50 ꢂC. After cooling to 10 ꢂC, compound 2 (3.30 g,
17.65 mmol) was added into the mixture and stirred for 2 h at 50 ꢂC. The resulting
mixture was poured into ice water (500 mL) and filtered to give the crude product.
The crude F was washed in 80 mL isopropanol to give a white solid. Yield: 73% (5.40 g);
1
HPLC: 97.81%. Mp: 263–266 ꢂC. H NMR (600 MHz, CDCl3) d 7.56 (d, J ¼ 2.4 Hz, 1H),
7.33 (d, J ¼ 8.4 Hz, 1H), 7.30 (d, J ¼ 1.8 Hz, 1H), 7.23 (dd, J ¼ 8.4 Hz, 1.8 Hz, 1H), 7.12
(d, J ¼ 8.4 Hz, 1.8 Hz, 1H), 7.0 (dd, J ¼ 8.4 Hz, 1.8 Hz, 1H), 6.38 (br, 1H), 4.29 (t,
J ¼ 5.4 Hz, 2H), 3.85 (m, 2H), 1.53 (s, 9H); 13C NMR (150 MHz, CDCl3) d 162.63,
159.37, 151.15, 147.86, 147.20, 144.32, 141.29, 130.12, 129.25, 124.13, 120.81, 118.80,
116.55, 110.86, 109.26, 84.54, 47.88, 42.50, 27.98. HRMS (ESI): m/z calcd. for
C21H20Cl2N4O4 [M þ H]þ: 463.0934, found 463.0936.
2-((5-Chloro-1,3-benzoxazol-2-yl)amino)ethylamine bis-MSA salt (compound G). Compound
3 (3.00g, 9.63mol) was dissolved in THF (30mL) and the solution cooled to 5 ꢂC. Methane
sulfonic acid (2.77g, 28.85mmol) was then added drop-wise and the resulting mixture
stirred for 3 h at 60ꢂC. The reaction was cooled to room temperature and filtered. The solid
was washed with THF (3 ꢃ 10mL) to give white solid. Yield: 96% (3.72g); HPLC: 99.78%.
1
mp: 210 ꢁ 212 ꢂC. H NMR (600 MHz, D2O) d 7.36 (d, J ¼ 9 Hz, 1H), 7.32 (d, J ¼ 2.4 Hz,
1H), 7.22 (dd, J ¼ 9 Hz, 2.4 Hz, 1H), 3.80 (t, J ¼ 6 Hz, 2H), 3.29 (t, J ¼ 6 Hz, 2H), 2.69 (s,
6H); 13C NMR (150MHz, D2O) d 159.95, 144.48, 132.72, 130.77, 124.03, 113.33, 111.67,
40.06, 38.42, 38.18. HRMS (ESI): m/z calcd. for C9H10ClN3O [Mþ H]þ: 212.0585,
found 212.0582.
4-((2-Amino-ethyl)-(5-chlorobenzoxazol-2-yl)amino)butan-2-ol (compound H). Compound 6
(20 g, 52.42 mmol) was dissolved in solvent (300 mL DCM þ 300 mL MeOH) and the
solution cooled to ꢁ10 ꢂC. NaBH4 (2.97 g, 78.63 mmol) was then added and the result-
ing mixture stirred for 1 h. Saturated NH4Cl aq. (100 mL) was then added to quench
the reaction, which was then concentrated in vacuo to remove organic solvent. The
mixture was then extracted with DCM (3 ꢃ 100 mL) and the organic extracts were com-
bined and washed with water (2 ꢃ 200 mL), dried over anhydrous NaSO4, filtered and
evaporated under reduced pressure to give the crude intermediate as a white solid,
which was used in the next step without any further purification H-1 (18.50 g, 92.5%).
Reaction mixture of compound H-1 (5.00 g) and HCl aq. (4 mol/L) (50 mL) was stirred
for 48 h at room temperature. The pH of the reaction solution was adjusted to 9 with
NaOH aq. (4 mol/L). The mixture was then extracted with DCM (3 ꢃ 100 mL) and the
organic extracts were combined and washed with water, dried over anhydrous Na2SO4,
filtered and evaporated under reduced pressure to give compound H as an oil. Yield:
1
64% (2.3 g); HPLC: 99.17%. H NMR (400 MHz, DMSO-d6) d 7.28 (d, J ¼ 2 Hz, 1H),
7.14 (d, J ¼ 8 Hz, 1H), 6.97 (dd, J ¼ 8 Hz, 2 Hz, 1H,), 4.02–3.95 (m, 2H), 3.80–3.72 (m,
1H), 3.66–3.59 (m, 1H), 3.52–3.44 (m, 1H), 3.02 (t, J ¼ 6.4 Hz 2H), 1.93–1.84 (m, 1H),
1.65–1.56 (m, 1H), 1.22(d, J ¼ 8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 163.96, 147.31,

2236
X. LV ET AL.
143.99, 129.45, 120.34, 116.15, 109.26, 63.38, 51.52, 46.57, 40.37, 37.71, 23.08. HRMS
(ESI): m/z calcd. for C13H18ClN3O2 [M þ H]þ: 284.1160, found 284.1165.
1
The materials of H NMR, 13C NMR, HRMS and HPLC Spectra of A, B, C, D, E, F,
G, H and 1 can be found via the “Supplementary Material” section of this
article’s webpage.
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