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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
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/[Link].0c00299 • Publication Date (Web): 14 Sep 2020
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Page 1 of 22 Organic Process Research & Development

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Facile Preparation of 4-(4-Nitrophenyl)morpholin-3-
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one via the Acid-catalyzed Selective Oxidation of 4-
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(4-Nitrophenyl)morpholine by Sodium Chlorite as
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20 the Sole Oxidant
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25 Chaoyang Liu a, Tao Yu a, Tiannuo Yang a, Haozhou Sun a, Cheng Qin a, Qiang Jia b
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29 and Changhu Chu a
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32 a Engineering
33 Research Centre of Pharmaceutical Process Chemistry, Ministry of Education;
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35 Shanghai Key Laboratory of New Drug Design; School of Pharmacy, East China University of
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37 Science and Technology, 130 Meilong Road, Shanghai 200237, People’s Republic of China
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40 b
41 Seasons Biotechnology (Taizhou) Co., Ltd., 21 Jiutiao Road, Jiaojiang District, Taizhou,
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43 Zhejiang 318000, People’s Republic of China
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47 TOC graphic
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1
2
3 O
4 NaClO2
5 O N NO2
O N NO2
cat. AcOH
6
7 rt-50oC
8 O
9 FeCl3/Charcoal
10 O N NH2
80% hydrazine
11 ethanol, reflux
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16 ABSTRACT: 4-(4-nitrophenyl)morpholin-3-one and 4-(4-aminophenyl) morpholin-3-one are
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19 the key intermediates for rivaroxaban synthesis. A facile and economic efficient process has been
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developed for the preparation of these intermediates. An excellent yield of 4-(4-
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24 nitrophenyl)morpholine is obtained by condensing 4-chloronitrobenzene and morpholine, and 4-
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26 (4-nitrophenyl)morpholine is oxidized using inexpensive sodium chlorite to achieve a good yield
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of the corresponding 4-(4-nitrophenyl)morpholin-3-one. Finally, the key intermediate of
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31 rivaroxaban, 4-(4-aminophenyl) morpholin-3-one, is achieved by the iron (III)-catalyzed
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33 reduction of the nitro group with aqueous hydrazine. No high-cost materials were used, and the
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35 process did not require column purification.
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KEYWORDS: rivaroxaban; 4-(4-nitrophenyl)morpholin-3-one; oxidation; sodium chlorite.
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43 INTRODUCTION
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47 4-(4-nitrophenyl)morpholin-3-one (1) and 4-(4-aminophenyl) morpholin-3-one (2) are the key
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intermediates in the preparation of rivaroxaban (marketed as XARELTO), an oxazolidinone
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52 derivative anticoagulant, which displays remarkable therapeutic effects in the management of
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54 several diseases 1. (Scheme 1)
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4 Scheme 1. Synthetic routes of rivaroxaban
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O O O
8 O
9 O N NO2 Reduction O N NH2 ClCO2R
O N N OR
10 K2CO3 H
1
11 2 O
(S)
N (Z) or
12 O
O
13 (S)
(S)
N (Z) N Cl
14
OH
15 O
16 O
O O
17 O N NH OH O O
18 O N N H
19 N N Cl
S
20 Rivaroxaban
O
O
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24 The intermediate 1 can be transformed to the corresponding 2 easily via nitro reduction reaction,
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26 and compound 2 is usually used as the starting material for the preparation of rivaroxaban2.
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Several methods for the synthesis of compound 1 have been reported. Bayer AG reported the
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31 condensation of 3-morpholinone with 1-fluoro-4-nitrobenzene in the presence of t-BuOK or NaH
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33 in NMP to give 1 with lower yield (17.4%) 3. An alternative route was applied to achieve
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35 precursor 2 directly by coupling 3-morpholinone with 4-halogen-aniline (4-bromo aniline or 4-
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38 iodo aniline) with good yield 2a. However, in both cases, 3-morpholinone is the key material, but
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40 it is difficult to obtain due to its low yield 4, thereby increasing the cost of the whole process.
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42 (Scheme 2)
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46 Scheme 2. Synthetic routes of intermediates 1 and 2.
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1
2
3 O
O
4
5 O N NO2
Reduction O N NH2
6 nd
7 1 Ba iga 2
se /L
8 /N C uI e NH2
9 F NO2 MP H as
N O b
10 X X = Br or I
11 O
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Other routes to obtain intermediates 1 and 2 have also been reported. The coupling of
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17 bromobenzene with 2-amino ethanol yielded 2-phenylamino ethanol, which was condensed with
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19 methyl 2-chloro acetate, and subsequently nitrated to achieve 1. Alternatively, compound 1 was
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also prepared by the condensation of 4-bromo nitrobenzene with 2-amino ethanol, followed by
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24 cyclization with methyl 2-chloro acetate. Both methods displayed low efficiency because of two
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26 reactive sites existing in both reactants, resulting in a complicated reaction system.5 (Scheme 3)
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30 Scheme 3. Alternative synthetic routes of intermediate 1.
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34 Br
HN O NO2
35 H 2N OH Cl
36 OH nitration
O
CuI N O
37 89% yield 83% yield
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39 Br O
O N O
40 HN Cl
41 H 2N OH OH O O
42 1
43 NO2
44 NO2
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Several processes have been reported for the transformation of cyclic amines to corresponding
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50 lactams via the chemoselective and regioselective oxidation of C−H bonds directly adjacent to a
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52 cyclic amine. In 2009, a patent showed an oxidation protocol for preparing compound 1 (Scheme
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4, equation 1) 3. In this case, large amounts of heavy metal oxidants, KMnO4, were utilized;
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3 however, this protocol is not environment friendly and is thus unfit for industry use. In 2014,
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6 Milstein et al. showed that cyclic amines can be transformed to lactams via ruthenium-catalyzed
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8 dehydrogenation (Scheme 4, equation 2); however, completing this transformation involves
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10 harsh reaction conditions and an air sensitive and precious metal catalyst 6. Ferric chloride-
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catalyzed oxidation cyclic amines offered a lower cost process for obtaining lactams, (Scheme 4,
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15 equation 3) but the substrate scope is currently limited due to the use of a strong peroxide
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17 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) 8; however, the
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22 catalyst loading is too large, and gold catalyst costs high, and the catalyst preparation is tedious.
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24 From an environmental perspective, the transient metal-free process is promising. In 2017,
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26 Talbot et al. developed a metal-free, chemoselective, and regioselective lactam formation method
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29 using molecular iodine as oxidant to oxidize cyclic amine (Scheme 4, equation 5) 9. However,
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31 this process uses a large amount of iodine and sodium bicarbonate, which produces too much
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33 waste. In 2018, Sartillo-Piscil et al. reported TEMPO-catalyzed oxidation of piperazines and
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morpholines under transition-metal-free conditions (Scheme 4, equation 6)10. This protocol uses
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38 low-cost and environmentally friendly oxidants, including sodium chlorite and sodium
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40 hypochlorite. Herein, we applied this catalytic reaction system to transform 4-(4-
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nitrophenyl)morpholine to 4-(4-nitrophenyl)morpholin-3-one 1.
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46 Scheme 4. Processes for the transformation of amines to their corresponding amides
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50 via chemoselective and regioselective oxidation
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3 O
4 1) 3eq KMnO4, 3eq BnEt3N+Cl-
DCM reflux, 15h
5 1) O N NO2 O N NO2
2) aq. Na2SO3
6 39% yield
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8 catalyst 1-5mol%
9 R n NaOH, 0-6mol% n
2) R + H N
10 O 2 Cl
N
dioxane:H2O=1:1(v:v) N catalyst Ru H
11 H H P OC P
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14 5mol% N CO2H R
R O
15 3) 5mol% FeCl3
16 R N R
R N R
17 3eq PhCO3t-Bu
18 50oC, 24h O
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20 N Au/Al2O3 N
4)
21 O2, 1 atm, H2O
22 100oC, 24h O
23 n n
24 5) R N X 7.5eq I2, 10 eq NaHCO3
R N X
25 aq THF, rt
26 R R
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O
28 6) 0.1 eq TEMPO, 3eq NaClO2
29 R N O 3eq NaH2PO4, 0.7 eq NaClO R N O
30 CH3CN, 0oC
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However, use of a TEMPO-catalyzed oxidation system in industrial processes has obvious
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36 disadvantages, as it involves a high-cost TEMPO catalyst and produces high amounts of
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40 waste salts. Furthermore, the complex reaction system would cause reaction control problems.
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43 The mixture of sodium chlorite and bleach appears unstable, which may lead to spray incidents
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45 11. As such, we describe here a novel acid-catalyzed oxidation of 4-(4-nitrophenyl) morpholine to
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1 under mild conditions, by using the low-cost and environmentally friendly sodium chlorite as
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50 the sole oxidant. (Scheme 5)
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7 Scheme 5. Oxidation route for the preparation of intermediate 1 and 2.
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11 NO2
a) heating b) NaClO2
12 O NH + O N NO2
solvent free cat. Acid
13 Cl
Rt-50oC
14 3
15 O
O
16 c) FeCl3/Charcoal
17 O N NO2 80% hydrazine O N NH2
18 ethanol, reflux
19 1 2
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21 Reaction conditions: a, morpholine (1mol), 4-chloro nitrobenzene (0.2mol), Na2CO3
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23 (0.12mol), 100°C, 4.5h; b, NaClO2 (300mol%), acetic acid (30% mol) c,
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25 FeCl3/Charcoal(15 mol%), aq. hydrazine (500mol%), reflux.
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27 RESULTS AND DISCUSSION
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4-(4-Nitrophenyl)morpholine (3) is prepared via the condensation of 4-chloro nitrobenzene with
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34 morpholine under neat conditions. Other 4-halogen nitrobenzene, such as 4-bromo-nitrobenzene,
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36 4-fluoro-nitrobenzene and 4-iodo-nitrobenzene are suitable for preparing 4-(4-
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38 nitrophenyl)morpholine 12. In the next step, we explored the oxidation of 4-(4-nitrophenyl)
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41 morpholine (Table 1). When the oxidation reaction was performed according to the reference
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43 reaction condition10, 98% of the substrate (3) was consumed. Aside from the generated target
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45 product 4-(4-nitrophenyl) morpholine-3-one, two side products (1a and 1b) were detected,
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suggesting that side chlorination reaction also occurred (Table 1, entry 1). Further increasing the
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50 reaction temperature (from 0°C to room temperature) expedited this oxidation reaction
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52 dramatically with almost the same regioselectivity (Table 1, entry 2). Given that TEMPO is an
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expensive catalyst, which would be destroyed in reaction conditions to form impurities, we
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3 performed the reaction without TEMPO. Almost the same result was achieved (Table 1, entry
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6 3). Further experiment shows that both TEMPO and sodium hypochlorite could cause chloride
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8 (1a) formation and resulted in better selectivity without using TEMPO and sodium hypochlorite
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10 as additives (Table 1, entries 4 and 5). The buffer NaH2PO4 is the key species for this reaction,
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because it acts as acid to adjust the reaction system’s pH. No reaction was observed when only
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15 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
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22 O
23
NaClO2,additive
24 O 2N N O + 1a + 1b
O 2N N O
25
CH3CN
26 3 1
27 O
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O 2N N O O 2N N O
29 major impurities
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Cl Cl
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1a 1b
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34 Entry Additive (mol) Temp. (°C) T (h) Conv.(%) b Molar ratiob
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1:1a:1b
37 NaH2PO4 NaClO TEMPO
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39 1 3 equiv. 0.7 equiv. 0.1 equiv. 0-r.t 18h >98 86:7:6
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41 2 3 equiv. 0.7 equiv. 0.1 equiv. 25 9h >98 88:7:4
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43 3 3 equiv. 0.7 equiv. 0 25 10.5h >98 86:8:5
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45 4 3 equiv. 0 0.1 equiv. 25 10h >98 90:4:5
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47 5 3 equiv. 0 0 25 3h >99 94:3:2
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49 6 0 0.7 equiv. 0 25 3h 0 nr
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7 0 0 0.1 equiv. 25 3h 0 nr
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52 8 0 0 0 25 3h 0 nr
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a Reaction conditions: unless specified, a mixture of 2 (5 mmol), NaClO2(15 mmol) in
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water(6 mL), in CH3CN (15 mL) was stirred . b Conversions and yields based on
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7 HPLC (area normalization).
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NaH2PO4, Na2HPO4 and Na3PO4 usually act as buffers in most reactions. NaH2PO4 was
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12 replaced with Na2HPO4 and Na3PO4 in this oxidation reaction, but no reaction is occurred (Table
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14 2, entries 1 and 2), This result may be attributed to the difference in pH of the reaction system:
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16 Na2HPO4, 10.26, Na3PO4, 12.6, and NaH2PO4 , 4.12-4.24. Thus, we believed that the acidic
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19 condition is critical for this reaction. Furthermore, excessive amounts of NaH2PO4 in this
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21 reaction would lead to large amount of solid waste. Thus, several acid additives were screened
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23 for this cyclic amine oxidation reaction. This reaction was completed in 45 min with low
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selectivity by using 1.5 equiv. of acetic acid (Table 2, entry 3). Decreasing the amount of acetic
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28 acid can increase selectivity (Table 2, entries 4 and 5), and 0.3 equiv. acetic acid resulted in the
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30 best conversion and selectivity in 4 h (Table 2, entry 6). HPLC indicated that the reaction with
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0.2 equiv. of acetic acid was only completed after 4 h, suggesting that the reaction was slow
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35 overall. Table 2, entry 7). Other acids, such as formic acid and phosphoric acid could also
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37 promote this reaction to consume all starting materials (Table 2, entries 8 and 9), but oxidation
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39 reaction with formic acid as an additive showed poor selectivity. The high reaction temperature
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42 would accelerate the reaction rate, and the reaction could be completed in 2h at 50 °C in the
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44 presence of 0.3 equiv. of acetic acid (pH 5.23 to 7.42) with good inversion rate and selectivity
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46 (Table 2, entry 10).
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Finally, the amount of oxidant was screened (Table 3). Two equiv. of sodium chlorite was
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52 enough to consume all substrates; however, both reaction rates and selectivity were low (4h,
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54 83%) (Table 3, entry 1). Increasing the amount of oxidant could enhance selectivity (Table 3,
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3 entry 2), and more than 3 equiv. of sodium chlorite resulted in the best selectivity (Table 3,
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6 entries 3 and 4).
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21 Table 2. Screening additive acids in amine oxidation reactions
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25 Entry Additive(mol) T (h) Conv.(%)b Molar ratio b
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1:1a:1b
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30 1 Na2HPO4(3 equiv.) overnight 0 nr
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33 2 Na3PO4(3 equiv.) overnight 0 nr
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35 3 CH3CO2H(1.5 equiv.) 0.75h >99 82:12:6
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38 4 CH3CO2H(1 equiv.) 1h >99 87:9:4
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40 5 CH3CO2H (0.5 equiv.) 3h >99 91:6:3
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43 6 CH3CO2H(0.3 equiv.) 4h >99 94:3:2
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7 CH3CO2H (0.2 equiv.) 7h >99 90:5:3
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48 8 HCO2H(0.3 equiv.) 5h 96 89:3:3
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51 9 H3PO4 (0.2 equiv.) 2h >99 96:3: 1
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53 10 CH3CO2H(0.3 equiv.) a, 2h >99 96:2:2
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56 a All reactions were performed at 50°C; b determined by area normalization on HPLC
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4 Table 3. Screening the amount of sodium chlorite
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6 Entry Amount of sodium chlorite Time Molar ratio b
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9 (mol) 1:1a:1b
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11 1 2 equiv. 4.0h 83:14:3
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14 2 2.5 equiv. 3.0h 90:8:2
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3 3 equiv. 2.0h 96:2:2
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19 4 4 equiv. 1.5h 97:2:1
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a Reaction conditions: unless specified, a mixture of 2 (5 mmol) and CH3CO2H (1.5
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mmol) was dissolved in CH3CN (10mL) and stirred at 50°C; then, NaClO2 in water
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25 (3.5mL) was added dropwise; b determined by area normalization on HPLC
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27 With the optimized reaction condition (3 equiv. of sodium chlorite, and 0.3 equiv. of acetic
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30 acid in acetonitrile), the oxidation reaction profile was established by using the HPLC yield
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32 (1/1a/1b). As shown in Figure 1, the oxidation reaction rate is dramatically faster than the
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34 chlorination reaction rate. The reaction was completed in 2.5 h, and the total amounts of 1a and
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37 1b were not obviously increased.
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40 Figure 1 HPLC yield (1/1a/1b) with reaction time
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34 Furthermore, 1a can be prepared by chlorinating 3 with sodium hypochlorite in acidic
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36 conditions with good yield. When 1a is loaded in this oxidation reaction system, it can be
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39 oxidized smoothly to corresponding 1b with 86% yield (HPLC purity, 98%). The control
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41 experimental shows that 1 cannot be chlorinated to 1b with sodium hypochlorite in acidic
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43 conditions.
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With the easily prepared intermediate 1, the reduction of the nitro group in 1 was also
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49 investigated (Scheme 5). The known method uses Pd on charcoal to catalyze hydrogenation.
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51 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 13. We used iron(III)-charcoal catalyzed reduction
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56 of nitro group with aqueous hydrazine as reductant; however, one pot reaction resulted in the
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3 morpholin-3-one ring opening compound 2a as the main product. In the iron(III)-hydrazine
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6 reduction system, the real active species is diimide, which is formed via in situ oxidation of
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8 hydrazine by iron (III). Then, hydrazine was added dropwise to the reaction, and the side product
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10 was dramatically decreased.
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14 Scheme 5 FeCl3 catalyzed aqueous hydrazine reduction of intermediate 1 to 2.
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16 O O
17 O 2N NH
FeCl3/Charcoal
18 +
O N NO2 80% hydrazine O N NH2
19 H2N NH O
20 1 ethanol, reflux 2
2a O
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23 We have developed a facile and convenient process of preparing 4-(4-nitrophenyl) morpholin-
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25 3-one, which can be further reduced to its corresponding 4-(4-aminophenyl) morpholin-3-one.
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27 Our process involves low-cost and easily available materials. Furthermore, working up the
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30 reaction in the whole process is quite convenient, and column chromatography is not needed.
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32 The product can be obtained via a simple slurry and filtration, and is suitable for industrial
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34 applications.
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38 EXPERIMENTAL SECTION
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41 General Procedures. Reverse-phase HPLC was performed on an agilent 1260 series HPLC
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43 instrument using the following methods. Zorbax sb-c18 RP (150mm × 4.6mm, 3.5),
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46 Conditions: flow rate 1 ml/min; 30oC; mobile phase: (A) water, (B) acetonitrile; (C) methanol;
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48 gradient: 0–4 min, 65-10% A, 25-80% B, 10% C; 4-7min. , 10% A, 80% B, 10% C; 7-14min. ,
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50 10-65% A, 80-25% B, 10% C; 14-16min., 65% A, 25% B, 10% C; 230 nm UV detector;
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53 Retention times are uncorrected; Molar ratios are determined by area normalization.
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3 4-Nitrophenyl morpholine (3). A mixture of p-nitrochlorobenzene (31.5g, 0.2mol),
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6 morpholine (87g, 1mol) and sodium carbonate (12.7g, 0.12mol) in a 500ml round bottom flask
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8 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.
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13 After that, 200mL water was added to this residue, and stirred for a few moments. All solid
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15 products were collected by filtration, rinsed with 50mL water and dried under vacuum to afford
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4-nitrophenyl morpholine (3). Yellow solid (isolated yield: 99%); 1H NMR (400 MHz, CDCl3) δ
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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
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22 MHz, CDCl3) δ 154.77, 139.25, 125.87, 112.90, 66.28, 47.32. MS (ES-API）[M+1]+= 209
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25 4-(4-Nitrophenyl)morpholin-3-one (1): a solution of 4-nitrophenyl morpholine (20.8 g, 0.1
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27 mol), acetic acid (1.8 g, 0.03 mol) in acetonitrile (200 ml) was added into a 1000 ml three port
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29 round bottom flask, and it was heated at 50 ℃ . Then a solution of sodium chlorite (more than
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32 80%, 33.8 g, 0.3mol) in 65 ml water was added dropwise in 20 min. The reaction system
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34 gradually turned to brown red, then light yellow. TLC and HPLC showed that the reaction was
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completed in 2.5 h. The reaction was quenched with aqueous saturated sodium sulfite, and the
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39 organic layer was separated. Removal of most of volatile left slurries, and the solid was collected
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41 by filtration rinsed with small amount water and dried, it could be used in the next step without
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43 further purification. 1, Light yellow solid (isolated yield: 91%, purity 99%, HPLC);1H NMR
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46 (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 =
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4.8Hz, 2H), 3.85 (t, J = 4.8Hz, 2H); 13C NMR (101 MHz,CDCl3) δ 166.79, 146.73, 145.40,
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50 124.69, 124.54, 68.64 , 63.94, 48.87; MS (ES-API ） [M+1]+ = 223. Side products 1a and 1b
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53 were isolated from mother liquid, and purified on a silica gel (petroleum ether/ ethyl acetate as
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55 eluent). 4-(2-chloro-4-nitrophenyl)morpholine (1a):Yellow solid (isolated 120 mg, yield: 0.5%)
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3 ; 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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6 = 9.2 Hz, 1H), 3.89 (t, J = 4.8 Hz, 4H), 3.21 (t, J = 4.8 Hz, 4H); 13C NMR (101 MHz,CDCl3) δ
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8 154.50, 142.43, 127.67 , 126.70, 123.45, 119.26, 66.71, 50.99; MS (ES-API）[M+1]+ = 243; 4-
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(2-chloro-4-nitrophenyl)morpholine-3-one(1b): Light yellow solid (isolated 230mg, yield:
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13 0.9%); 1H 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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15 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).; 13C NMR
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(101 MHz, CDCl3) δ 166.47, 147.64, 144.21, 133.85, 130.45, 126.03 , 123.18 , 68.45, 63.93,
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20 49.26; MS: [M+1]+= 257. After the oxidation reaction was performed for 2.5 hours, the reaction
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22 mixture was detected by HPLC. HPLC spectrum can be found in supporting information.
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24 Retention times for 1, 1a, 1b and 3 are 6.2min., 8.9min., and 6.7min. and 7.7min. respectively.
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27 1a could be prepared according this procedure: a mixture of 4-nitrophenyl morpholine (1.04 g ,5
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29 mmol) and acetic acid(0.09g, 1.5mmol) in 10 ml acetonitrile was heated to 40℃ on a water bath，
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then sodium hypochlorite (7% activated Cl, 8.34g, 9mmol) was added dropwise. After 4-
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34 nitrophenyl morpholine was consumed (TLC), the reaction was quenched by adding aqueous
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36 saturated sodium sulfite. After most solvent was removed by evaporation, a large amount of solid
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was precipitated. This solid was collected by filtration, and dried to obtain 1a. (yield 88%, purity
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41 98%, HPLC) .
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43 1b can be prepared from 1a (1.21g, 5mmol) with same procedure as the preparation of 1. Yield,
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45 86%, HPLC purity 98%.
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48 When the mixture of 1 and acetic acid in acetonitrile was treated with sodium hypochlorite (7%
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50 activated Cl), no reaction occured.
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4 4-(4-Aminophenyl)morpholin-3-one (2): To a solution of 4-(4-nitrophenyl)morpholin-3-
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7 one (11.1 g, 0.05 mol) in 150mL ethanol, anhydrous ferric chloride (1.215 g, 7.5 mmol) and
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10 activated carbon (5 g) were added subsequently. Then the reaction was heated to reflux, 15.6 g
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13 of hydrazine hydrate (80% aqueous solution, 0.25 mol) was added dropwise in 1h. TLC and
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15 HPLC detection showed that this reaction could be completed in 2h. Charcoal was removed by
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17 filtration, and the solution was concentrated on a rotatory evaporator to leave a residue, which
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was recrystallized from acetonitrile to afford pure 2. White solid (isolated yield: 93%, purity
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22 98%, HPLC); 1H NMR (400 MHz,DMSO-d6) δ 6.96 (d, J = 5.6 Hz, 2H), 6.56 (d, J = 5.6 Hz,
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24 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
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MHz, CDCl3) δ 165.74 , 147.31 , 130.21 , 126.39, 113.65 , 67.68 , 63.51 , 49.58. MS(ES-API）
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29 [M+1]+= 193
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31 If the reaction performed in one pot, a yellow solid was formed, the structure was confirmed to
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34 be the ring opening product 2a, 2-(2-((4-nitrophenyl)amino)ethoxy) acetohydrazide: Yellow
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36 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,
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38 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
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40 13C
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Hz, 2H); NMR (101 MHz, DMSO-d6) δ 167.98 , 154.45 , 135.64 , 126.17 , 110.79, 69.28 ,
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43 69.01 , 42.04. MS(ES-API）[M+1]+= 255
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46 ASSOCIATED CONTENT
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50 Supporting Information.
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4 Spectrums for some compounds. This material are available free of charge.
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7 AUTHOR INFORMATION
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12 Corresponding Author
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E-mail: Changhu Chu， chuch@[Link]. Qiang Jia， charlie@[Link]
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20 Present Addresses
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1 Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of
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27 Education; Shanghai Key Laboratory of New Drug Design; School of Pharmacy, East
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31 China University of Science and Technology, 130 Meilong Road, Shanghai 200237,
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34 People’s Republic of China
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2 Seasons Biotechnology (Taizhou) Co., Ltd., 21 Jiutiao Road, Jiaojiang District,
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42 Taizhou, Zhejiang 318000, People’s Republic of China.
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Notes
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50 The authors declare no competing financial interest.
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55 ACKNOWLEDGMENT
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4 This work was supported by the National Natural Science Foundation of China
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7 (21372081, 21172072).
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