Facile preparation of 4-(4-nitrophenyl)morpholin-3-one via the acid-catalyzed selective oxidation of 4-(4-nitrophenyl)morpholine by sodium chlorite as the sole oxidant

Article abstract of DOI:10.1021/acs.oprd.0c00299

4-(4-Nitrophenyl)morpholin-3-one and 4-(4-aminophenyl) morpholin-3-one are the key intermediates for rivaroxaban synthesis. A facile and economically efficient process has been developed for the preparation of these intermediates. Excellent yield of 4-(4-nitrophenyl)morpholine is obtained by condensing 4-chloro nitrobenzene and morpholine, and 4-(4- nitrophenyl)morpholine is oxidized using inexpensive sodium chlorite to achieve a good yield of the corresponding 4-(4- nitrophenyl)morpholin-3-one. Finally, the key intermediate of rivaroxaban, 4-(4-aminophenyl) morpholin-3-one, is achieved by the iron(III)-catalyzed reduction of the nitro group with aqueous hydrazine. No high-cost materials were used, and the process did not require column purification.

Full text of DOI:10.1021/acs.oprd.0c00299

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Full Paper
Facile Preparation of 4-(4-Nitrophenyl)morpholin-3-
one via the Acid-catalyzed Selective Oxidation of 4-(4-
Nitrophenyl)morpholine by Sodium Chlorite as the Sole Oxidant
Chaoyang Liu, Tao Yu, Tiannuo Yang, Haozhou Sun, Cheng Qin, Qiang Jia, and Changhu Chu
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00299 • Publication Date (Web): 14 Sep 2020
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Facile Preparation of 4-(4-Nitrophenyl)morpholin-3-
one via the Acid-catalyzed Selective Oxidation of 4-
(4-Nitrophenyl)morpholine by Sodium Chlorite as
the Sole Oxidant
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Chaoyang Liu a, Tao Yu a, Tiannuo Yang a, Haozhou Sun a, Cheng Qin a, Qiang Jia b
and Changhu Chu a
a Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of Education;
Shanghai Key Laboratory of New Drug Design; School of Pharmacy, East China University of
Science and Technology, 130 Meilong Road, Shanghai 200237, People’s Republic of China
b Seasons Biotechnology (Taizhou) Co., Ltd., 21 Jiutiao Road, Jiaojiang District, Taizhou,
Zhejiang 318000, People’s Republic of China
TOC graphic
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O
NaClO2
NO2
O
N
O
N
NO2
cat. AcOH
rt-50oC
O
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FeCl3/Charcoal
O
N
NH2
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80% hydrazine
ethanol, reflux
ABSTRACT: 4-(4-nitrophenyl)morpholin-3-one and 4-(4-aminophenyl) morpholin-3-one are
the key intermediates for rivaroxaban synthesis. A facile and economic efficient process has been
developed for the preparation of these intermediates. An excellent yield of 4-(4-
nitrophenyl)morpholine is obtained by condensing 4-chloronitrobenzene and morpholine, and 4-
(4-nitrophenyl)morpholine is oxidized using inexpensive sodium chlorite to achieve a good yield
of the corresponding 4-(4-nitrophenyl)morpholin-3-one. Finally, the key intermediate of
rivaroxaban, 4-(4-aminophenyl) morpholin-3-one, is achieved by the iron (III)-catalyzed
reduction of the nitro group with aqueous hydrazine. No high-cost materials were used, and the
process did not require column purification.
KEYWORDS: rivaroxaban; 4-(4-nitrophenyl)morpholin-3-one; oxidation; sodium chlorite.
INTRODUCTION
4-(4-nitrophenyl)morpholin-3-one (1) and 4-(4-aminophenyl) morpholin-3-one (2) are the key
intermediates in the preparation of rivaroxaban (marketed as XARELTO), an oxazolidinone
derivative anticoagulant, which displays remarkable therapeutic effects in the management of
several diseases 1. (Scheme 1)
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Scheme 1. Synthetic routes of rivaroxaban
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O
N
O
N
O
N
O
Reduction
ClCO2R
K2CO3
O
NO2
O
NH2
O
N
OR
Cl
H
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1
(S)
2
(Z)
N
O
or
O
O
(S)
(S)
N
(Z)
N
OH
O
O
N
O
O
O
NH OH
O
O
O
N
N
H
N
Cl
N
S
Rivaroxaban
O
O
The intermediate 1 can be transformed to the corresponding 2 easily via nitro reduction reaction,
and compound 2 is usually used as the starting material for the preparation of rivaroxaban2.
Several methods for the synthesis of compound 1 have been reported. Bayer AG reported the
condensation of 3-morpholinone with 1-fluoro-4-nitrobenzene in the presence of t-BuOK or NaH
3
in NMP to give 1 with lower yield (17.4%) . An alternative route was applied to achieve
precursor 2 directly by coupling 3-morpholinone with 4-halogen-aniline (4-bromo aniline or 4-
iodo aniline) with good yield 2a. However, in both cases, 3-morpholinone is the key material, but
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it is difficult to obtain due to its low yield , thereby increasing the cost of the whole process.
(Scheme 2)
Scheme 2. Synthetic routes of intermediates 1 and 2.
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O
O
N
Reduction
O
N
NH2
O
NO2
nd
2
Base/NMP
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1
8
9
NH2
CuI/Liga
base
H
N
F
NO2
O
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X
X = Br or I
O
Other routes to obtain intermediates 1 and 2 have also been reported. The coupling of
bromobenzene with 2-amino ethanol yielded 2-phenylamino ethanol, which was condensed with
methyl 2-chloro acetate, and subsequently nitrated to achieve 1. Alternatively, compound 1 was
also prepared by the condensation of 4-bromo nitrobenzene with 2-amino ethanol, followed by
cyclization with methyl 2-chloro acetate. Both methods displayed low efficiency because of two
reactive sites existing in both reactants, resulting in a complicated reaction system.5 (Scheme 3)
Scheme 3. Alternative synthetic routes of intermediate 1.
Br
O
HN
Br
NO2
Cl
H2N
OH
OH
nitration
O
N
O
O
CuI
83% yield
89% yield
N
O
O
O
HN
Cl
H2N
OH
OH
O
1
NO2
NO2
Several processes have been reported for the transformation of cyclic amines to corresponding
lactams via the chemoselective and regioselective oxidation of C−H bonds directly adjacent to a
cyclic amine. In 2009, a patent showed an oxidation protocol for preparing compound 1 (Scheme
3
4, equation 1) . In this case, large amounts of heavy metal oxidants, KMnO4, were utilized;
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however, this protocol is not environment friendly and is thus unfit for industry use. In 2014,
Milstein et al. showed that cyclic amines can be transformed to lactams via ruthenium-catalyzed
dehydrogenation (Scheme 4, equation 2); however, completing this transformation involves
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harsh reaction conditions and an air sensitive and precious metal catalyst . Ferric chloride-
catalyzed oxidation cyclic amines offered a lower cost process for obtaining lactams, (Scheme 4,
equation 3) but the substrate scope is currently limited due to the use of a strong peroxide
oxidant 7. The heterogeneous gold nanoparticle supported on alumina is a mild and
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chemoselective route for amide and lactam formation (Scheme 4, equation 4) ; however, the
catalyst loading is too large, and gold catalyst costs high, and the catalyst preparation is tedious.
From an environmental perspective, the transient metal-free process is promising. In 2017,
Talbot et al. developed a metal-free, chemoselective, and regioselective lactam formation method
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using molecular iodine as oxidant to oxidize cyclic amine (Scheme 4, equation 5) . However,
this process uses a large amount of iodine and sodium bicarbonate, which produces too much
waste. In 2018, Sartillo-Piscil et al. reported TEMPO-catalyzed oxidation of piperazines and
morpholines under transition-metal-free conditions (Scheme 4, equation 6)10. This protocol uses
low-cost and environmentally friendly oxidants, including sodium chlorite and sodium
hypochlorite. Herein, we applied this catalytic reaction system to transform 4-(4-
nitrophenyl)morpholine to 4-(4-nitrophenyl)morpholin-3-one 1.
Scheme 4. Processes for the transformation of amines to their corresponding amides
via chemoselective and regioselective oxidation
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O
N
1) 3eq KMnO4, 3eq BnEt3N+Cl-
DCM reflux, 15h
2) aq. Na2SO3
39% yield
1)
O
N
NO2
O
NO2
catalyst 1-5mol%
n
NaOH, 0-6mol%
n
R
R
+
2)
N
Ru
H2
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Cl
O
N
H
P
N
catalyst
dioxane:H2O=1:1(v:v)
H
H
P
OC
5mol%
R
N
CO2H
O
R
3)
5mol% FeCl3
R
N
R
R
N
R
3eq PhCO3t-Bu
50oC, 24h
O
Au/Al2O3
N
N
4)
5)
O2, 1 atm, H2O
100oC, 24h
O
n
X
n
X
7.5eq I2, 10 eq NaHCO3
aq THF, rt
R N
R N
R
R
O
0.1 eq TEMPO, 3eq NaClO2
6)
R N
O
3eq NaH2PO4, 0.7 eq NaClO
CH3CN, 0oC
R N
O
However, use of a TEMPO-catalyzed oxidation system in industrial processes has obvious
disadvantages, as it involves a high-cost TEMPO catalyst and produces high amounts of
waste salts. Furthermore, the complex reaction system would cause reaction control problems.
The mixture of sodium chlorite and bleach appears unstable, which may lead to spray incidents
11. As such, we describe here a novel acid-catalyzed oxidation of 4-(4-nitrophenyl) morpholine to
1 under mild conditions, by using the low-cost and environmentally friendly sodium chlorite as
the sole oxidant. (Scheme 5)
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Scheme 5. Oxidation route for the preparation of intermediate 1 and 2.
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NO2
b) NaClO2
a) heating
+
Cl
O
NH
O
N
NO2
cat. Acid
Rt-50oC
solvent free
3
O
N
O
c) FeCl3/Charcoal
O
NH2
O
N
NO2
80% hydrazine
ethanol, reflux
2
1
Reaction conditions: a, morpholine (1mol), 4-chloro nitrobenzene (0.2mol), Na2CO3
(0.12mol), 100°C, 4.5h; b, NaClO2 (300mol%), acetic acid (30% mol) c,
FeCl3/Charcoal(15 mol%), aq. hydrazine (500mol%), reflux.
RESULTS AND DISCUSSION
4-(4-Nitrophenyl)morpholine (3) is prepared via the condensation of 4-chloro nitrobenzene with
morpholine under neat conditions. Other 4-halogen nitrobenzene, such as 4-bromo-nitrobenzene,
4-fluoro-nitrobenzene and 4-iodo-nitrobenzene are suitable for preparing 4-(4-
nitrophenyl)morpholine 12. In the next step, we explored the oxidation of 4-(4-nitrophenyl)
morpholine (Table 1). When the oxidation reaction was performed according to the reference
reaction condition10, 98% of the substrate (3) was consumed. Aside from the generated target
product 4-(4-nitrophenyl) morpholine-3-one, two side products (1a and 1b) were detected,
suggesting that side chlorination reaction also occurred (Table 1, entry 1). Further increasing the
reaction temperature (from 0°C to room temperature) expedited this oxidation reaction
dramatically with almost the same regioselectivity (Table 1, entry 2). Given that TEMPO is an
expensive catalyst, which would be destroyed in reaction conditions to form impurities, we
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performed the reaction without TEMPO. Almost the same result was achieved (Table 1, entry
3). Further experiment shows that both TEMPO and sodium hypochlorite could cause chloride
(1a) formation and resulted in better selectivity without using TEMPO and sodium hypochlorite
as additives (Table 1, entries 4 and 5). The buffer NaH2PO4 is the key species for this reaction,
because it acts as acid to adjust the reaction system’s pH. No reaction was observed when only
NaClO or TEMPO was used, as well as without any additives. (Table 1, entries 6, 7 and 8)
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Table 1. Critical parameters of the oxidation reaction
O
NaClO2,additive
+ 1a
O
1b
+
O2N
N
O2N
N
O
CH3CN
N
1
3
O
N
O2N
O
O2N
O
major impurities
Cl
Cl
1a
1b
Entry
Additive (mol)
NaH2PO4 NaClO TEMPO
Temp. (°C) T (h) Conv.(%) b Molar ratiob
1:1a:1b
1
2
3
4
5
6
7
8
3 equiv. 0.7 equiv. 0.1 equiv.
3 equiv. 0.7 equiv. 0.1 equiv.
0-r.t
25
25
25
25
25
25
25
18h
9h
>98
>98
>98
>98
>99
0
86:7:6
88:7:4
86:8:5
90:4:5
94:3:2
nr
3 equiv. 0.7 equiv.
0
10.5h
10h
3h
3 equiv.
0
0.1 equiv.
3 equiv.
0
0
0
0
0
0.7 equiv.
0
0.1 equiv.
0
3h
0
0
3h
0
nr
3h
0
nr
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a Reaction conditions: unless specified, a mixture of 2 (5 mmol), NaClO2(15 mmol) in
b
water(6 mL), in CH3CN (15 mL) was stirred . Conversions and yields based on
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HPLC (area normalization).
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NaH2PO4, Na2HPO4 and Na3PO4 usually act as buffers in most reactions. NaH2PO4 was
replaced with Na2HPO4 and Na3PO4 in this oxidation reaction, but no reaction is occurred (Table
2, entries 1 and 2), This result may be attributed to the difference in pH of the reaction system:
Na2HPO4, 10.26, Na3PO4, 12.6, and NaH2PO4 , 4.12-4.24. Thus, we believed that the acidic
condition is critical for this reaction. Furthermore, excessive amounts of NaH2PO4 in this
reaction would lead to large amount of solid waste. Thus, several acid additives were screened
for this cyclic amine oxidation reaction. This reaction was completed in 45 min with low
selectivity by using 1.5 equiv. of acetic acid (Table 2, entry 3). Decreasing the amount of acetic
acid can increase selectivity (Table 2, entries 4 and 5), and 0.3 equiv. acetic acid resulted in the
best conversion and selectivity in 4 h (Table 2, entry 6). HPLC indicated that the reaction with
0.2 equiv. of acetic acid was only completed after 4 h, suggesting that the reaction was slow
overall. Table 2, entry 7). Other acids, such as formic acid and phosphoric acid could also
promote this reaction to consume all starting materials (Table 2, entries 8 and 9), but oxidation
reaction with formic acid as an additive showed poor selectivity. The high reaction temperature
would accelerate the reaction rate, and the reaction could be completed in 2h at 50 °C in the
presence of 0.3 equiv. of acetic acid (pH 5.23 to 7.42) with good inversion rate and selectivity
(Table 2, entry 10).
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Finally, the amount of oxidant was screened (Table 3). Two equiv. of sodium chlorite was
enough to consume all substrates; however, both reaction rates and selectivity were low (4h,
83%) (Table 3, entry 1). Increasing the amount of oxidant could enhance selectivity (Table 3,
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entry 2), and more than 3 equiv. of sodium chlorite resulted in the best selectivity (Table 3,
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entries 3 and 4).
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Table 2. Screening additive acids in amine oxidation reactions
Entry Additive(mol)
T (h)
Conv.(%)b Molar ratio b
1:1a:1b
1
2
3
4
5
6
7
8
9
10
Na2HPO4(3 equiv.)
overnight 0
overnight 0
nr
Na3PO4(3 equiv.)
nr
CH3CO2H(1.5 equiv.)
CH3CO2H(1 equiv.)
0.75h
1h
>99
82:12:6
87:9:4
91:6:3
94:3:2
90:5:3
89:3:3
96:3: 1
96:2:2
>99
>99
>99
>99
96
CH3CO2H (0.5 equiv.) 3h
CH3CO2H(0.3 equiv.) 4h
CH3CO2H (0.2 equiv.) 7h
HCO2H(0.3 equiv.)
H3PO4 (0.2 equiv.)
5h
2h
>99
>99
CH3CO2H(0.3 equiv.) a, 2h
a
All reactions were performed at 50°C; b determined by area normalization on HPLC
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Table 3. Screening the amount of sodium chlorite
Entry Amount of sodium chlorite Time Molar ratio b
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(mol)
1:1a:1b
4.0h 83:14:3
3.0h 90:8:2
2.0h 96:2:2
1.5h 97:2:1
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1
2
3
4
2 equiv.
2.5 equiv.
3 equiv.
4 equiv.
a Reaction conditions: unless specified, a mixture of 2 (5 mmol) and CH3CO2H (1.5
mmol) was dissolved in CH3CN (10mL) and stirred at 50°C; then, NaClO2 in water
(3.5mL) was added dropwise; b determined by area normalization on HPLC
With the optimized reaction condition (3 equiv. of sodium chlorite, and 0.3 equiv. of acetic
acid in acetonitrile), the oxidation reaction profile was established by using the HPLC yield
(1/1a/1b). As shown in Figure 1, the oxidation reaction rate is dramatically faster than the
chlorination reaction rate. The reaction was completed in 2.5 h, and the total amounts of 1a and
1b were not obviously increased.
Figure 1 HPLC yield (1/1a/1b) with reaction time
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Furthermore, 1a can be prepared by chlorinating 3 with sodium hypochlorite in acidic
conditions with good yield. When 1a is loaded in this oxidation reaction system, it can be
oxidized smoothly to corresponding 1b with 86% yield (HPLC purity, 98%). The control
experimental shows that 1 cannot be chlorinated to 1b with sodium hypochlorite in acidic
conditions.
With the easily prepared intermediate 1, the reduction of the nitro group in 1 was also
investigated (Scheme 5). The known method uses Pd on charcoal to catalyze hydrogenation.
However, a large amount of catalyst (5-20 weight%, 5% palladium on charcoal) is needed,
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thereby increasing the higher production cost . We used iron(III)-charcoal catalyzed reduction
of nitro group with aqueous hydrazine as reductant; however, one pot reaction resulted in the
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morpholin-3-one ring opening compound 2a as the main product. In the iron(III)-hydrazine
reduction system, the real active species is diimide, which is formed via in situ oxidation of
hydrazine by iron (III). Then, hydrazine was added dropwise to the reaction, and the side product
was dramatically decreased.
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Scheme 5 FeCl3 catalyzed aqueous hydrazine reduction of intermediate 1 to 2.
O
O
O2N
NH
FeCl3/Charcoal
+
O
N
NH2
O
N
NO2
80% hydrazine
ethanol, reflux
H2N NH
O
1
2
2a
O
We have developed a facile and convenient process of preparing 4-(4-nitrophenyl) morpholin-
3-one, which can be further reduced to its corresponding 4-(4-aminophenyl) morpholin-3-one.
Our process involves low-cost and easily available materials. Furthermore, working up the
reaction in the whole process is quite convenient, and column chromatography is not needed.
The product can be obtained via a simple slurry and filtration, and is suitable for industrial
applications.
EXPERIMENTAL SECTION
General Procedures. Reverse-phase HPLC was performed on an agilent 1260 series HPLC
instrument using the following methods. Zorbax sb-c18 RP (150mm × 4.6mm, 3.5),
Conditions: flow rate 1 ml/min; 30oC; mobile phase: (A) water, (B) acetonitrile; (C) methanol;
gradient: 0–4 min, 65-10% A, 25-80% B, 10% C; 4-7min. , 10% A, 80% B, 10% C; 7-14min. ,
10-65% A, 80-25% B, 10% C; 14-16min., 65% A, 25% B, 10% C; 230 nm UV detector;
Retention times are uncorrected; Molar ratios are determined by area normalization.
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4-Nitrophenyl morpholine (3). A mixture of p-nitrochlorobenzene (31.5g, 0.2mol),
morpholine (87g, 1mol) and sodium carbonate (12.7g, 0.12mol) in a 500ml round bottom flask
was stirred at 100 ℃for 4.5h, TLC and HPLC detection showed that p-nitrochlorobenzene was
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almost consumed. Then most of the unreacted morpholine was recovered by vacuum distillation.
After that, 200mL water was added to this residue, and stirred for a few moments. All solid
products were collected by filtration, rinsed with 50mL water and dried under vacuum to afford
4-nitrophenyl morpholine (3). Yellow solid (isolated yield: 99%); 1H NMR (400 MHz, CDCl3) δ
8.22-8.13 (m, 2H), 6.93-6.84 (m, 2H), 3.95-3.86 (m, 4H), 3.44-3.36 (m, 4H); 13C NMR (101
MHz, CDCl3) δ 154.77, 139.25, 125.87, 112.90, 66.28, 47.32. MS (ES-API）[M+1]+= 209
4-(4-Nitrophenyl)morpholin-3-one (1): a solution of 4-nitrophenyl morpholine (20.8 g, 0.1
mol), acetic acid (1.8 g, 0.03 mol) in acetonitrile (200 ml) was added into a 1000 ml three port
round bottom flask, and it was heated at 50℃. Then a solution of sodium chlorite (more than
80%, 33.8 g, 0.3mol) in 65 ml water was added dropwise in 20 min. The reaction system
gradually turned to brown red, then light yellow. TLC and HPLC showed that the reaction was
completed in 2.5 h. The reaction was quenched with aqueous saturated sodium sulfite, and the
organic layer was separated. Removal of most of volatile left slurries, and the solid was collected
by filtration rinsed with small amount water and dried, it could be used in the next step without
further purification. 1, Light yellow solid (isolated yield: 91%, purity 99%, HPLC);1H NMR
(400 MHz,CDCl3) δ 8.28 (d, J = 8.8Hz, 2H), 7.61 (d, J = 8.8Hz, 2H), 4.40 (s, 2H), 4.08 (t, J =
4.8Hz, 2H), 3.85 (t, J = 4.8Hz, 2H); 13C NMR (101 MHz,CDCl3) δ 166.79, 146.73, 145.40,
124.69, 124.54, 68.64 , 63.94, 48.87; MS (ES-API）[M+1]+ = 223. Side products 1a and 1b
were isolated from mother liquid, and purified on a silica gel (petroleum ether/ ethyl acetate as
eluent). 4-(2-chloro-4-nitrophenyl)morpholine (1a):Yellow solid (isolated 120 mg, yield: 0.5%)
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; 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 2.8 Hz, 1H), 8.11 (dd, J = 9.2, 2.8 Hz, 1H), 7.05 (d, J
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= 9.2 Hz, 1H), 3.89 (t, J = 4.8 Hz, 4H), 3.21 (t, J = 4.8 Hz, 4H); C NMR (101 MHz,CDCl3) δ
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154.50, 142.43, 127.67 , 126.70, 123.45, 119.26, 66.71, 50.99; MS (ES-API）[M+1]+ = 243; 4-
(2-chloro-4-nitrophenyl)morpholine-3-one(1b): Light yellow solid (isolated 230mg, yield:
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1
0.9%); H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 2.4 Hz, 1H), 8.24 (dd, J = 8.4, 2.4Hz, 1H),
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7.51 (d, J = 8.4 Hz, 1H), 4.41 (s, 2H), 4.15 – 4.07 (m, 2H), 3.74 (t, J = 5.0 Hz, 2H).; C NMR
(101 MHz, CDCl3) δ 166.47, 147.64, 144.21, 133.85, 130.45, 126.03 , 123.18 , 68.45, 63.93,
49.26; MS: [M+1]+= 257. After the oxidation reaction was performed for 2.5 hours, the reaction
mixture was detected by HPLC. HPLC spectrum can be found in supporting information.
Retention times for 1, 1a, 1b and 3 are 6.2min., 8.9min., and 6.7min. and 7.7min. respectively.
1a could be prepared according this procedure: a mixture of 4-nitrophenyl morpholine (1.04 g ,5
mmol) and acetic acid(0.09g, 1.5mmol) in 10 ml acetonitrile was heated to 40℃ on a water bath，
then sodium hypochlorite (7% activated Cl, 8.34g, 9mmol) was added dropwise. After 4-
nitrophenyl morpholine was consumed (TLC), the reaction was quenched by adding aqueous
saturated sodium sulfite. After most solvent was removed by evaporation, a large amount of solid
was precipitated. This solid was collected by filtration, and dried to obtain 1a. (yield 88%, purity
98%, HPLC) .
1b can be prepared from 1a (1.21g, 5mmol) with same procedure as the preparation of 1. Yield,
86%, HPLC purity 98%.
When the mixture of 1 and acetic acid in acetonitrile was treated with sodium hypochlorite (7%
activated Cl), no reaction occured.
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4-(4-Aminophenyl)morpholin-3-one (2): To a solution of 4-(4-nitrophenyl)morpholin-3-
one (11.1 g, 0.05 mol) in 150mL ethanol, anhydrous ferric chloride (1.215 g, 7.5 mmol) and
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activated carbon (5 g) were added subsequently. Then the reaction was heated to reflux, 15.6 g
of hydrazine hydrate (80% aqueous solution, 0.25 mol) was added dropwise in 1h. TLC and
HPLC detection showed that this reaction could be completed in 2h. Charcoal was removed by
filtration, and the solution was concentrated on a rotatory evaporator to leave a residue, which
was recrystallized from acetonitrile to afford pure 2. White solid (isolated yield: 93%, purity
1
98%, HPLC); H NMR (400 MHz,DMSO-d6) δ 6.96 (d, J = 5.6 Hz, 2H), 6.56 (d, J = 5.6 Hz,
2H), 5.13 (s, 2H), 4.14 (s, 2H), 3.91 (t, J = 3.2 Hz, 2H), 3.58 (t, J = 3.2 Hz, 2H); 13C NMR (101
MHz, CDCl3) δ 165.74 , 147.31 , 130.21 , 126.39, 113.65 , 67.68 , 63.51 , 49.58. MS(ES-API）
[M+1]+= 193
If the reaction performed in one pot, a yellow solid was formed, the structure was confirmed to
be the ring opening product 2a, 2-(2-((4-nitrophenyl)amino)ethoxy) acetohydrazide: Yellow
solid; 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.00(d, 2H, J = 9.2 Hz), 7.38 (t, J = 5.2 Hz,
1H), 6.70 (d, 2H, J = 9.2 Hz), 4.27 (s, 2H), 3.93 (s, 2H), 3.60 (t, J = 5.2 Hz, 2H), 3.39 (t, J = 5.2
Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 167.98 , 154.45 , 135.64 , 126.17 , 110.79, 69.28 ,
69.01 , 42.04. MS(ES-API）[M+1]+= 255
ASSOCIATED CONTENT
Supporting Information.
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Spectrums for some compounds. This material are available free of charge.
AUTHOR INFORMATION
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Corresponding Author
E-mail: Changhu Chu， chuch@ecust.edu.cn. Qiang Jia， charlie@seasonsbio.com
Present Addresses
1 Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of
Education; Shanghai Key Laboratory of New Drug Design; School of Pharmacy, East
China University of Science and Technology, 130 Meilong Road, Shanghai 200237,
People’s Republic of China
2
Seasons Biotechnology (Taizhou) Co., Ltd., 21 Jiutiao Road, Jiaojiang District,
Taizhou, Zhejiang 318000, People’s Republic of China.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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This work was supported by the National Natural Science Foundation of China
(21372081, 21172072).
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