An improved and practical route for the synthesis of enzalutamide and potential impurities study

Article abstract of DOI:10.1016/j.cclet.2016.09.007

An improved and practical synthesis of enzalutamide was accomplished in five steps. Starting from 4-bromo-2-fluoro-benzonic acid, a methyl esterification, Ullmann ligation, methyl esterification, ring closing reaction and final methyl amidation provided the target in 35% total yield with 99.8% purity. Five identified impurities were also synthesized. This efficient and economical procedure avoids the use of highly toxic reagents and multiple recrystallization operations, which is suitable for further industrialization.

Full text of DOI:10.1016/j.cclet.2016.09.007

G Model
CCLET 3824 1–5
Chinese Chemical Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
1
2
Original article
3
4
An improved and practical route for the synthesis of enzalutamide and
potential impurities study
a,b
a,
a
a
b
a,
5
Q1 Ai-Nan Zhou , Bonan Li *, Lejun Ruan , Yeting Wang , Gengli Duan , Jianqi Li *
a
6
7
Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Shanghai 201203, China
b
School of Pharmacy, Fudan University, Shanghai 201203, China
A R T I C L E I N F O
A B S T R A C T
Article history:
An improved and practical synthesis of enzalutamide was accomplished in five steps. Starting from 4-
bromo-2-fluoro-benzonic acid, a methyl esterification, Ullmann ligation, methyl esterification, ring
closing reaction and final methyl amidation provided the target in 35% total yield with 99.8% purity. Five
identified impurities were also synthesized. This efficient and economical procedure avoids the use of
highly toxic reagents and multiple recrystallization operations, which is suitable for further
industrialization.
Received 27 June 2016
Received in revised form 31 August 2016
Accepted 7 September 2016
Available online xxx
Keywords:
Enzalutamide
New route
High purity
Impurity
ß 2016 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
8
9
1. Introduction
Three main routes for the synthesis of enzalutamide have been 31
reported. The first was undertaken by Sawyers et al. [14] in 32
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14
15
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17
18
19
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Enzalutamide (1, Fig. 1) is a new type of androgen receptor (AR)
antagonist [1] that was developed by Medivation Inc for the
treatment of castration-resistant prostate cancer [2,3] (CRPC), a
serious cancer that afflicts men [4]. The oral capsule of
Enzalutamide [5] was approved by the FDA for sale in August
2012. According to the statistics of the American Cancer Society
[6], 217,730 new patients were diagnosed with prostate cancer by
hospitals and clinics in the United States of America in 2010. Of
these, 32,050 patients died as a result of prostate cancer within
2 years. Bicalutamide [7], flutamide [8] and abiraterone [9] were
used to treat prostate cancer before the launch of enzalutamide.
These drugs controlled CRPC effectively in only a small proportion
of patients and caused some obvious side effects [10], such as
hypertension, atrial fibrillation and hypokalemia. The cancer
became resistant to these treatments in many patients after a
period of about 2 years [11–13]. The development of enzalutamide
provided a better choice for the treatment of CRPC, achieving sales
of up to 1 billion dollars in 2013 and even better returns after that
year. Research into new processes to produce the active
pharmaceutical ingredient (API) enzalutamide is important and
meaningful to continue delivery of this important drug.
2006. One obvious deficiency on this route is the very low yield of 33
the last step, which would make producing the API costly at 34
industrial scale. Song et al. [15] made a small improvement to this 35
route using ethyl 2-bromobutyrate in place of 2-cyano-2-propanol, 36
but this route remained unattractive for the production of 1. Five 37
years later, Thompson and co-workers [16] provided an alternative 38
route to synthesize 1, which improves on the original synthesis by 39
removing the oxidation and reduction reactions. However, the 40
yields of the last two steps are too low for economical kilo scale 41
production of the API. Scientists from Medivation Inc. [17] also 42
improved the second route and published their results in 2012. This 43
synthesis overcame the poor yields of the final steps in the first and 44
second routes, which justifies the use of high toxic iodomethane at 45
a late stage of the synthesis and makes the third route more 46
reasonable than the procedures of the first and second routes for 47
commercial manufacture, but the crude product of which also need 48
to be recrystallized for 2–3 times by isopropanol to get qualified 49
API. A new route is needed for the efficient synthesis of 1 using 50
moderate and environmentally friendly conditions and reagents. 51
Herein we report a new five-step route to 1 that avoids highly toxic 52
reagents and multiple recrystallization processes.
53
2. Results and discussion
54
*
Corresponding authors.
Our new route [18,19] began with 4-bromo-2-fluoro-benzonic 55
acid (2a) (Scheme 1). 5 g of 2a were subjected to a methyl 56
E-mail addresses: pkuthulbn@gmail.com (B. Li), lijianqib@126.com (J. Li).
http://dx.doi.org/10.1016/j.cclet.2016.09.007
1
001-8417/ß 2016 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: A.-N. Zhou, et al., An improved and practical route for the synthesis of enzalutamide and potential
impurities study, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.09.007

G Model
CCLET 3824 1–5
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A.-N. Zhou et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
Fig. 1. Structure of enzalutaminde 1.
Scheme 2. Possible reaction mechanism of the fourth step on the new route.
entry 6). DMF was investigated as an alternative to DMSO but only
a trace amount of the solid was crystalized from the mother
solution, that is probably because DMSO is a highly polar solvent
which is easier to be removed completely by water washing than
that of DMF (Table 1, entry 7). We increased the reaction scale to
over 1 kg and lowered the ratio of DMSO from 33% to 16% of the
total solvent to obtain a 82% yield of the product after a 24-h
reaction (Table 1, entry 8). Extending the reaction time to 36 or
48 h decreased the yields of the product by 5% and 12%,
respectively (Table 1, entries 9 and 10).
Although the intermediate 2f was successfully synthesized in
82% using the optimized conditions, it was unclear why the
reaction required two equivalents of 2e. A likely mechanism to
explain this phenomenon is shown in Scheme 2. The lone pair
electrons on the nitrogen atom of compound 2d attack the most
positively charged carbon on the isothiocyanate group of
compound 2e in the first step to form an active intermediate
2fa. An intramolecular ring closing reaction of 2fa, using the lone
pair electrons of the nitrogen atom on the thiourea group to attack
the methyl ester group, forms the stable five-member ring of the
main product 2f. A molecule of methanol is released by this
process, which is a strong nucleophile and reacts with another
molecule of compound 2e to form methyl N-(3-trifluoromethyl-4-
cayno-)-phenylcarbonate (impurity A) as a side product. Fortu-
nately, impurity A was easily to be removed by recrystallization
with isopropanol to get qualified 2f. This possible mechanism
explains why two molecules of reactant 2e were consumed to form
product 2f and one molecule of side product impurity A.
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
Scheme 1. The first three steps of the new route to enzalutamide.
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
esterification reaction catalyzed by sulfuric acid in methanol under
reflux in the first step [20] to obtain methyl 4-bromo-2-fluoro-
benzoate (2b) in 95% yield, which was easily isolated as a white
solid by pouring the reaction solution into ice water after 24 h. The
second step was an Ullmann reaction [21–23] for the ligation of 2b
with 2-amino-2-methylpropionic acid to give compound 2c, which
was reacted with thionyl chloride in refluxing methanol to obtain
3603 g of intermediate 2-fluoro-4-[(2-methoxy-1,1-dimethyl-2-
oxoethyl)amino]-methyl ester (2d) in a total yield of 51% for the
first three steps.
Intermediate 2d was reacted with 2e [24,25] in the fourth step
of our new route. The reaction conditions for this step were
optimized by the following steps (Table 1). The initial conditions
used 1.0 mol of compounds 2d and 2e in a solution of dimethyl
sulfoxide (DMSO) and isopropyl acetate at 95 8C to give only 30% of
the desired product (Table 1, entry 1). Increasing the stoichiometry
of compound 2e resulted in higher yields (Table 1, entries 2–4). The
final ratio of reactant 2e was fixed at two equivalents relative to 2d
to ensure a cost-effective process. Lowering the reaction tempera-
ture to 80 8C dropped the yield to 57% (Table 1, entry 5). Ethyl
acetate has similar properties to isopropyl acetate but was not
suitable to achieve high yields because the lower boiling point of
this solvent prevented an adequate reaction temperature (Table 1,
Table 1
Optimization of the fourth step of the new route to enzalutamide.
a
b
c
Entry
2d:2e (molar ratio)
Solvents (v/v)
Temp. (8C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
1:1
1:1.5
1:2
1:3
1:2
1:2
1:2
1:2
1:2
1:2
DMSO:AcIPA = 1:2
DMSO:AcIPA = 1:2
DMSO:AcIPA = 1:2
DMSO:AcIPA = 1:2
DMSO:AcIPA = 1:2
DMSO:AcOEt =1:2
DMF:AcIPA = 1:2
DMSO:AcIPA = 1:5
DMSO:AcIPA = 1:5
DMSO:AcIPA = 1:5
95
95
95
95
80
65
95
95
95
95
24
24
24
24
24
24
24
24
36
48
30
45
65
68
57
45
Trace
82
77
1
0
70
a
b
c
For entries 1–7 the amount of 2d was 269 g (1.0 mol) and for entries 8–10, the amount of 2d was increased to 1200 g (4.46 mol).
For entries 1–7, the total solvent volume was 810 mL and for entries 8–10 the total solvents volume was 3600 mL.
Isolated yields.
Please cite this article in press as: A.-N. Zhou, et al., An improved and practical route for the synthesis of enzalutamide and potential
impurities study, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.09.007

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A.-N. Zhou et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
3
Table 2
Optimization of the last step of the new route to enzalutamide.
a
b
c
d
Entry
Form of methylamine
CH NH
Temp. (8C)
Time (h)
Conversion of 2f (%)
Yield (%)
Purity of crude 1 (%)
1
2
3
4
5
6
7
8
9
3
2
ÁHCl
r.t.
24
48
48
48
48
4
<5
–
–
2.0 M in THF
2.0 M in MeOH
33% in MeOH
r.t.
ꢀ30
ꢀ30
ꢀ60
ꢀ80
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
–
–
r.t.
–
–
r.t.
–
–
30% in H
40% in H
40% in H
40% in H
40% in H
40% in H
40% in H
40% in H
40% in H
40% in H
40% in H
40% in H
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
r.t.
–
–
r.t.
55
60
60
70
70
72
76
78
75
84
86
96.66
97.85
98.99
99.16
99.24
99.44
99.65
99.59
99.75
99.80
99.78
15 Æ 3
10 Æ 3
7
10
12
16
19
24
48
22
22
22
5
0
Æ 2
Æ 2
1
1
1
1
1
1
1
0
1
2
3
4
5
6
À5 Æ 1
À10 Æ 1
À15 Æ 1
À8 Æ 1
À8 Æ 1
À8 Æ 1
a
b
c
Entries 1–14 were carried out on 100 g scales, and entries 15 and 16 were carried out on a 1.4 kg scale.
Conversion of 2f was monitored by TLC.
Isolated yield.
d
HPLC analysis.
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
The fifth and final step was a methyl amidation reaction of 2f to
The optimal reaction temperature for this reaction was investigat- 135
ed. Temperatures between 15 8C and À15 8C were screened and 136
required extending the reaction time as the temperature was 137
lowered. The purity of crude 1 was 97.85% when the reaction was 138
carried out at 15 8C for 7 h (Table 2, entry 7). The purity improved 139
to 98.99% and 99.16% (Table 2, entries 8 and 9) for reactions at 140
10 8C and 5 8C, respectively. However, these crude products were 141
needed to be recrystallized two to three times to meet ICH 142
guidelines and more than half of the product was lost to these 143
multiple recrystallization processes. Improving the purity of the 144
crude product and removing the need for multiple recrystallization 145
operations was deemed critical to allow industrialization of our 146
process. Lowering the reaction temperature to 0 8C or À5 8C, the 147
purity was improved to 99.24% and 99.44%, respectively (Table 2, 148
entries 10 and 11). The purity was further improved to 99.65% by 149
decreasing the temperature to À10 8C (Table 2, entry 12). Lowering 150
the temperature further to À15 8C extended the reaction time to 151
48 h without improving the crude purity of 1 (Table 2, entry 13). 152
The final temperature was fixed at À8 8C and the reaction was 153
completed in 22 h with a crude purity of 99.75% (Table 2, entry 14). 154
Two parallel scale-up reactions at a kilogram scale synthesized 1 155
with high crude purity and satisfactory yield at À8 8C in 22 h 156
(Table 2, entries 15 and 16). These conditions provide a practical 157
give 1. Initial experiments investigating the solvents tetrahydro-
furan (THF), methanol (MeOH), ethanol (EtOH), acetone or
dichloromethane (DCM) indicated that this reaction was most
successful in THF. Two key points that affect the degree of reaction
completion and purity of the final product are the different forms
of methylamine and reaction temperature. We began screening
tests with different forms of methylamine (Table 2). Methylamine
hydrochloride failed to react because of low solubility in THF and
weak nucleophilicity (Table 2, entry 1). Solutions of 2.0 mol/L
methylamine as a free base in THF and MeOH were attempted to
improve solubility (Table 2, entries 2 and 3), but the conversions
were around 30%, probably because of the low concentrations of
the methylamine solutions. Higher concentrations of 33% methyl-
amine in MeOH and 30% methylamine in water were used to
increase conversion, but large amounts of 2f remained at the end of
the reaction, even when the reaction time was extended to 48 h at
room temperature (Table 2, entries
4 and 5). The most
concentrated methylamine solution commercially available is a
40% aqueous solution. Fortunately, the reactant 2f was not
detected by TLC when treated with the 40% methylamine aqueous
solution for 4 h at room temperature and the product was obtained
in 55% yield (Table 2, entry 6). HPLC analysis indicated that many
unidentified impurities were also formed using these conditions.
The concentrations of impurities must be minimized to the
accepted levels set by the International Conference on Harmoni-
zation (ICH) to ensure the safety and quality of a drug substance.
route for further industrialization of our process.
158
Besides impurity A, four other impurities were identified from 159
the reaction process and synthesized afterwards. Impurity B and C 160
are probably formed by the side reactions of hydrolyzation and 161
Fig. 2. Four observed impurities in the new route.
Please cite this article in press as: A.-N. Zhou, et al., An improved and practical route for the synthesis of enzalutamide and potential
impurities study, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.09.007

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A.-N. Zhou et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
1
1
1
1
1
1
1
1
62
63
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65
66
67
68
69
aminolyzation during the process from 2f to 1. The impurities D
and E were also identified in the process probably because the
sulfur atom is easily to be oxidized to oxygen or hydroxide group,
which were synthesized and characterized, the structures and
relative retention time of which are listed in Fig. 2. The relative
retention time of enzalutamide is on 28.00 min. The synthesis
procedures and characterization data are provided in the
Supporting information.
was used for the next reaction step without any further separation
or purification process.
220
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230
231
232
233
234
235
236
237
238
239
240
241
242
Crude 2c was dissolved in methanol (20.0 L) and thionyl
chloride (1.0 L) was added dropwise at 0 8C over 30 min. The
solution was heated under reflux for 12 h, concentrated in vacuo,
and the residue dissolved in ethyl acetate (20.0 L). The ethyl
acetate solution was washed with saturated potassium carbonate
solution (10.0 L, three times), water (10.0 L, once) and saturated
sodium chloride solution (10.0 L, twice). The organic layer was
concentrated until about 15 L of ethyl acetate was removed, n-
heptane (5.0 L) was added and the solution was cooled in an ice
bath to precipitate the product. After 1 h, the solids were isolated
by filtration and dried in an oven at 60 8C overnight to afford 2d as
1
70
3. Conclusion
171
172
173
174
175
176
177
A novel approach to synthesize enzalutamide has been
established. This five-step process removes poor yielding steps
without the need for highly toxic chemicals and multiple
recrystallization processes, five impurities were also identified
and synthesized. Compared with the existing process, this
approach is the most efficient, economical and convenient route
to synthesize enzalutamide on a large scale.
white crystals (3088.0 g, 55.1% yield for two steps, 99.2% purity).
1
Mp 109.9–112.0 8C; H NMR (400 Hz, DMSO-d
6
):
d
1.48 (s, 6H),
3.63 (s, 3H), 3.74 (s, 3H), 6.13–6.17(dd, 1H, J = 14.8, 2.4 Hz), 6.29–
6.32 (dd, 1H, J = 8.8, 2.4 Hz), 7.04 (s, 1H), 7.63–7.59 (t, 1H,
1
3
J = 8.8 Hz); C NMR (100 Hz, DMSO-d
9.7 (d, JF-C = 20.0 Hz), 104.7 (d, JF-C = 10.0 Hz), 109.4, 133.3, 152.9
(d, JF-C = 10.0 Hz), 162.5, 164.2, 164.3 (d, JF-C = 10.0 Hz), 175.6;
6
): d 25.9, 51.8, 52.8, 57.0,
9
1
78
4. Experimental
+
MS(ESI): Calcd. for C13
4
H16FNO 269.1, found: 270.1 [M+H] ; Anal.
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
Nuclear magnetic resonance (NMR) spectra were recorded on a
Varian INOVA-400 spectrometer with TMS as an internal standard.
Chemical shifts (d values) and coupling constants (J values) are
Calcd. C13
N 5.08.
H16FNO : C 57.99, H 5.99, N 5.20; found: C 57.91, H 6.00,
4
given in ppm and Hz, respectively. ESI mass spectra were obtained
using on an Agilent 6210 TOF spectrometer. Elemental analyses
were performed on a MOD-1106 instrument and are consistent
with theoretical values within Æ0.3%. Uncorrected melting
points were determined on an electrothermal melting point
apparatus. Reaction progress and chemical purity were evaluated
by HPLC analysis using Waters symmetry C18 (5 mm,
250 mm  4.6 mm) column with a mobile phase A (MeOH + 0.05%
TFA) and B (0.3% TEA), 88:12 v/v; detection at 230 nm; flow rate:
1.0 mL/min; and temperature: 25 8C. TLC analyses were performed on
prepared HSGF254 TLC plates. Solvents and reagents were used as
received.
4.3. Synthesis of O-methyl-4-[3-(4-cyano-3-trifluoromethylphenyl)-
5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]-2-fluoro-benzonate
(2f)
243
244
245
Compound 2d (1200.0 g, 4.46 mol) and 4-cayno-3-trifluoro-
methyl-phenylisothiocyanate (2e, 2000.0 g, 8.77 mol) were added
to a mixture of dimethyl sulfoxide (DMSO, 600 mL) and isopropyl
acetate (AcIPA, 3.0 L) in a 10-L round-bottom flask with four necks
and the resulting solution was mixed well. The reaction was heated
to 95 8C for 24 h, then transferred into a separation vessel.
Isopropyl acetate (6.0 L) and water (3.0 L) were added to the deep-
brown reaction solution and the mixture stirred for 1 min.
Isopropanol (IPA, 600 mL) was added to break the emulsification
layer, and DMSO was washed out with the aqueous phase. These
operations were repeated three times to remove almost all of the
DMSO and the organic phase was concentrated in vacuo. Fresh
isopropanol (7.0 L) was added to the residue and mixed well. The
mixture was heated to 70 8C to fully dissolve the residue and then
cooled to 10 8C to precipitate the product. The yellow solids were
isolated by filtration and recrystallized from isopropanol (9.0 L)
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
1
94
4.1. Synthesis of methyl 4-bromo-2-fluoro-benzonate (2b)
195
196
197
198
199
200
201
202
203
204
4-Bromo-2-fluoro-benzonic acid (2a) (5.0 kg, 22.9 mol) was
charged to a 50-L round-bottom glass reaction vessel holding
methanol (20.0 L). Concentrated sulfuric acid (500 mL) was added
dropwise over 40 min. The reaction mixture was heated under
reflux for 12 h, poured into ice water (30 L) and the white solid
precipitate filtered. The product was dried by heating (less than
once to afford 2f as a white solid (1700.0 g, 82.0% yield, 99.7%
1
50 8C) in an oven overnight to afford 2b as white crystals (4851.1 g,
purity). Mp 152.0–154.0 8C; H NMR (400 Hz, DMSO-d
6
):
d
1.57 (s,
1
91.2% yield). Mp 60.0–61.0 8C; H NMR (400 Hz, DMSO-d
6
):
d
3.85
6H), 3.93 (s, 3H), 7.44 (dd, 1H, J = 1.6, 6.8 Hz), 7.54 (dd, 1H, J = 1.6,
13
(t, 3H, J = 8.5 Hz), 7.54–7.57 (dd, 1H, J = 8.8, 1.2 Hz), 7.68–7.71 (dd,
1H, J = 10.4, 1.2 Hz), 7.80–7.84 (t, 1H, J = 8.2 Hz).
6.8 Hz), 8.10–8.14 (m, 2H), 8.33 (s, 1H), 8.43 (d, 1H, J = 8.0 Hz);
NMR (100 Hz, DMSO-d ): 22.8, 52.6, 66.7, 108.7, 114.9, 119.1,
23.5, 126.2, 127.8 (d, JF-C = 10.0 Hz), 131.1 (q, JF-C = 30.0 Hz),
132.7, 133.9, 136.2, 137.8, 140.9, 159.6, 162.1, 163.3, 174.6, 179.9;
C
6
d
1
2
2
05
06
4.2. Synthesis of 2-fluoro-4-[(2-methoxy-1,1-dimethyl-2-
+
oxoethyl)amino]-methyl ester (2d)
15 4 3 3
MS(ESI): Calcd. for C21H F N O S 465.1, found: 466.1 [M+H] ;
Anal calcd.: C 54.19, H 3.25, N 9.03; found: C 53.98, H 3.24, N, 8.99.
207
208
209
210
211
212
213
214
215
216
217
218
219
2-Amino-2-methyl-propionic
1.5 equiv.), anhydrous copper monochloride (CuCl, 457.0 g,
4.6 mol, 0.2 equiv.), potassium carbonate (K CO 5768.0 g,
acid
(3527.0 g,
34.2 mol,
4.4. Synthesis of N-methyl-4-[3-(4-cyano-3-trifluoromethylphenyl)-
5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]-2-fluoro-benzamide
(enzalutamide, 1)
271
272
273
2
3
,
41.8 mol), and water (250 mL) were added to a solution of
compound 2b (4851.1 g, 20.9 mol) in DMF (15.0 L) and heated to
105 8C for 12 h. The color of the reaction system turned from deep
green to purple then to deep blue over this period. At the end of the
reaction the slurry was filtered, water (60.0 L) was added to the
deep-blue solution, and the mixture was neutralized with
saturated citric acid solution until the pH 3–4 and the solution
turned light blue. The solution was extracted with 2-methylte-
trahydrofuran (20.0 L Â 3) and the combined organic layers
concentrated in vacuo. The yellow residue (crude compound 2c)
Compound 2f (1500.0 g, 3.23 mol) was charged to a 10-L round-
bottom flask with four necks containing tetrahydrofuran (3.0 L)
and mixed well to dissolve all the solids. The solution was cooled to
À11 8C and a 40% methylamine aqueous solution (3.0 L) pre-cooled
to À10 8C was added dropwise over 40 min. The reaction
temperature was increased by 2–3 8C during the addition. The
reaction was kept at À8 Æ 1 8C for 22 h then quenched by adding
ethanol (3.0 L). The whole solution was concentrated in vacuo to
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impurities study, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.09.007

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CCLET 3824 1–5
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5
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remove the tetrahydrofuran, ethanol and more than half of the water.
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319
321
323
99.8% purity). Mp 198.2–199.1 8C; H NMR (400 Hz, DMSO-d
6
): d 1.56
[
(s, 6H), 2.82 (d, 3H, J = 4.0 Hz), 7.35 (dd, 1H, J = 8.0, 1.2 Hz), 7.43 (d, 1H,
J = 10.8 Hz), 7.81 (t, 1H, J = 8.4 Hz), 8.09 (dd, 1H, J = 8.4, 1.2 Hz), 8.29
13
(s, 1H), 8.38 (s, 1H), 8.39 (d,, 1H J = 8.0 Hz); C NMR (100 Hz, DMSO-
): d 23.0, 26.3, 66.4, 108.8, 115.0, 118.0, 122.8 (q, JCF3-C = 30.0 Hz),
125.1, 126.1, 128.0, 130.8, 131.2, 133.9, 136.2, 138.0, 138.4, 157.8 (d,
F-C = 10.0 Hz), 163.4, 174.7, 180.1. MS(ESI): Calcd. for C21
[
d
6
325
327
(
J
16 4 4 2
H F N O S
[
+
+
464.1, found: 465.1 [M+H] , 487.1 [M+Na] . Anal calcd. C 54.31, H
3.47, N 12.06, found: C 54.34, H 3.73, N 11.99.
3
329
3
331
333
335
337
[
[
[
2
95
Acknowledgments
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We thank the 2016 Shanghai Pujiang Talent Plan (No.
16PJ1432800) and China State Institute of Pharmaceutical Institute
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impurities study, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.09.007