An Improved Synthesis of Rivaroxaban

Full text of DOI:10.1080/00304948.2017.1291006

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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An Improved Synthesis of Rivaroxaban
Shaixiao Tian, Bo Tang, Minzhong Zhang, Qingjiao Gao, Bo Chen, Qinghua
Zhang & Guangyu Xu
To cite this article: Shaixiao Tian, Bo Tang, Minzhong Zhang, Qingjiao Gao, Bo Chen, Qinghua
Zhang & Guangyu Xu (2017) An Improved Synthesis of Rivaroxaban, Organic Preparations and
Procedures International, 49:2, 169-177
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Date: 20 April 2017, At: 13:28

Organic Preparations and Procedures International, 49:169–177, 2017
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2017.1291006
An Improved Synthesis of Rivaroxaban
Shaixiao Tian,1 Bo Tang,1 Minzhong Zhang,1 Qingjiao Gao,2
Bo Chen,2 Qinghua Zhang,2 and Guangyu Xu1
1Key Laboratory of Phytochemistry R&D of Hunan Province, College of
Chemistry and Chemical Engineering, Hunan Normal University, Changsha
410081, P. R. China
2Research and Development, Hunan Fangsheng Pharmaceuticals Limited,
Changsha 410205, P. R. China
Rivaroxaban (1) is a novel, oral, selective direct inhibitor of factor Xa developed by
Bayer Healthcare.1,2 It has been approved by the EMEA and FDA for the prevention of
venous thromboembolism in adult patients after total hip replacement or total knee
replacement surgery.3–6 Rivaroxaban is available on the market under the brand name
XareltoÒ in Europe and the US.
To date, several methods have been reported for the synthesis of rivaroxaban.2,7–21
Most of them share the use of 5-S-hydroxymethyl or 5-S-aminomethyl oxazolidinones (2
and 3 respectively) as key intermediates. However the 5-S-hydroxymethyl group must
first be activated as its sulfonate ester, then displaced with excess ammonia in a sealed
vessel13 or substituted with potentially explosive NaN3, followed by hydrogenation,14,15
to generate the corresponding aminomethyl group of rivaroxaban. As result of these prob-
lems, additional approaches to the synthesis of 5-(S)-aminomethyl oxazolidinone 3 have
been explored.2,16–21
The synthesis of rivaroxaban via 5-S-aminomethyl oxazolidinone 3 was originally
reported in patent WO 0147919 (Scheme 1).2
Received July 20, 2016; in final form October 19, 2016.
Address correspondence to Guangyu Xu, Key Laboratory of Phytochemistry R&D of Hunan
Province, College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha
410081, P. R. China. E-mail: gyxu@hunnu.edu.cn
169

170
Xu et al.
Scheme 1
Compound 6, obtained by the reaction of 4 with 5 in an ethanol/water mixture, was
treated with N,N’-carbonyldiimidazole (CDI) in the presence of a catalytic amount of
dimethylaminopyridine (DMAP) in THF as solvent to afford compound 7. Removal of
the phthalimido protecting group of 7 by reaction with aqueous methylamine gave 5-(S)-
aminomethyl oxazolidinone 3, which was subsequently acylated with 5-chlorothiophene-
2-carbonyl chloride (8) using pyridine as solvent and acid scavenger to afford rivaroxaban
(1) with HPLC purity of 100% after column chromatography. Berwe16 and Mali17 and
coworkers disclosed some optimization of reaction conditions described in the patent
WO 0147919 to make this process suitable for scale-up in a commercial plant. Unfortu-
nately, the difficulty in re-use of the phthalimide protecting group after hydrazinolysis or
aminolysis makes this process less green and cheap. Several other routes have been
reported on the synthesis of 5-(S)-aminomethyl oxazolidinone 3; however, there are some
drawbacks associated with the process described in these reports. These drawbacks
include the use of tedious chromatography for purification,18 use of potentially explo-
sive19 or flammable reagents during the reaction20 and low yields of the intermediate and
final product.21 Therefore there is a need for an improved preparation of rivaroxaban suit-
able for industrial application.
Scheme 2

Improved Synthesis of Rivaroxaban
171
The oxazolidinone ring is a crucial structural feature in many medicines, including
linezolid, rivaroxaban, and cethromycin. Inspired by the process to prepare linezolid,22,23
a similar protocol was adopted to building the oxazolidinone moiety of rivaroxaban. As
shown in Scheme 2, commercially available 4 was reacted with ethyl chloroformate in a
mixture of toluene and water using K2CO3 as acid scavenger to afford carbamate 9. Car-
bamate 9 has poor solubility in water and toluene which leads to ready isolation through
filtration. As it was reported that 4-chlorohydrin imine 10 was highly crystalline23, it was
selected as the second reaction partner for oxazolidinone formation. Accordingly the
cyclization of carbamate 9 with chlorohydrin imine 10 proceeded in refluxing CH2Cl2 in
the presence of lithium t-butoxide. The reaction was complete within 12 hours without
the formation of significant impurities. However, isolation and purification of the desired
imine 11 were problematic as it was prone to cleave to 3 during the work-up. To over-
come this problem, the isolation of imine 11 from the reaction mixture was not carried
out immediately when the reaction finished. The reaction mixture was acidified to pH 2–3
using a solution of aq. HCl and ethanol to precipitate 3 as the hydrochloride salt. It is
noteworthy to mention that the reaction using benzyl carbamate and methyl carbamate
gave the required product with 28% and 75% yields, respectively (Scheme 3).
Scheme 3
Salt 3¢HCl was dissolved in water and subjected to acylation with 5-chlorothiophene-
2-carbonyl chloride (prepared from 5-chlorothiophene-2-carboxylic acid 12) in toluene
using Na2CO3 according to the literature method.16 Rivaroxaban 1 was precipitated out
and recrystallized in good yield but also with the unexpected dichloro impurity A and
deschloro impurity B. It is obvious that these two impurities are derived from the raw
material 5-chlorothiophene-2-carboxylic acid, in which unreacted material and excess
chlorination byproduct are present. We found that the source of these two impurities
could be controlled in the starting material by choosing a different supplier.
The synthetic route shown in Scheme 2 has been used to manufacture several batches
of the API Rivaroxaban. HPLC analysis indicated the presence of two new impurities at
0.15 and 0.20 area% in several batches of rivaroxaban, identified as ‘impurity C’ and
‘impurity D’. Further work demonstrated that these two impurities were difficult to purge

172
Xu et al.
during the final recrystallization and suggested that upstream control would be important.
Impurities C and D were isolated from the mother liquor by silica gel column chromatog-
raphy, and their structures were confirmed by 1H NMR, 13C NMR and HRMS-ESI.
The impurity C was believed to arise from related impurities in the intermediate
3¢HCl. It is generally believed that there are small amounts of p-chlorobenzaldehyde in
chlorohydrin imine 10, where the carbonyl group could be attacked by the lithium salt of
4-aryl-3-morpholinone in the cyclization step to give 2-(1-hydroxyalkyl)-3-morpholinone
12 (Scheme 4). Similar nucleophilic attack on an aldehyde by a 3-morpholinone lithium
salt24 to form penultimate impurity C has been noted in the literature. After the amidation
of 12 with 5-chlorothiophene-2-carbonyl chloride, the impurity C was found to be present
at levels greater than 0.15% in the final product. Unfortunately, removal of p-chloroben-
zaldehyde from imine 10 by slurry wash or recrystallization proved difficult; however,
impurity 12 could be removed efficiently after the crude 3¢HCl was slurried with ethanol.
Scheme 4
The structure of impurity D as bis[4-(3-oxo-4-morpholinyl)phenyl]urea was also
confirmed by synthesis (Scheme 5), where impurity D was easily synthesized from 4-(4-
aminophenyl)morpholin-3-one 4 with CDI and matched unambiguously with the fraction-
ated sample of the impurity by 1H NMR and HPLC retention time.
Scheme 5
This impurity is generated during the carbamate formation of 9. The formation of impu-
rity D is possible by the aminolysis of carbamate 9 with 4-(4-aminophenyl)morpholin-3-
one under the given conditions. It was found that the use of an organic base, for example
Et3N or pyridine in CH2Cl2 or EtOAc, increased the formation of this impurity

Improved Synthesis of Rivaroxaban
173
drastically. When the reaction was carried out in a mixture of toluene and water using an
inorganic base such as Na2CO3 or K2CO3, the amount of this impurity could be mini-
mized to 0.35%. This impurity cannot be efficiently eliminated by recrystallization in the
carbamation and the next cyclization step due to its high crystallizability. Fortunately,
this impurity was almost insoluble in water, so we could remove it by filtration from
3¢HCl solution in water before the next amidation step.
In summary, we have developed a convenient synthesis of rivaroxaban in three steps
from 4-(4-aminophenyl)morpholin-3-one with one additional step to prepare chiral inter-
mediate chlorohydrin 10 (overall yield from 4 is 57.7%). Four impurities A-D of rivarox-
aban were characterized by NMR and MS and their mode of formation during the
preparation of rivaroxaban were also determined. In addition, the reaction sequences
were optimized to afford low concentrations of these impurities to levels accepted by
ICH guidelines.
Experimental Section
1
The H NMR and 13C NMR spectra were recorded in CDCl3 and DMSO-d6 using
€
Brucker 500 MHz NMR spectrometer; the chemical shifts are reported in d ppm relative
to TMS. The LC-MS and mass spectrum were recorded on a Waters XEVO LC-MS spec-
trometer. The melting points were determined by using the capillary method on an YRT-
3 melting point apparatus, which are uncorrected. HPLC analysis was performed on a
Shimadazu SPD-15C instrument with a UV detector using Agilent TC-C18 (250 mm £
4.6 mm, 5 mm) column. Mobile phase A: dissolve 0.79 g of ammonium bicarbonate in
1000 mL water and added 2.0 mL triethylamine, adjust the pH to 8.0 with formic acid.
Mobile phase B: acetonitrile. Gradient: 0 min: 80% A, 20% B; 10 min: 80% A, 20% B;
18 min: 68% A, 32% B; 44 min: 34% A, 66% B; 50 min: 34% A, 66% B; 50.1 min: 80%
A, 20% B; 60 min: 80% A, 20% B; UV detection at 250 nm; flow rate: 0.7 mL/min; Col-
umn oven temperature: 25ꢀC. Chiral purity was estimated using Chiralcel OD-H (250 £
4.6 mm), 5m column; mobile phase comprising a mixture of n-hexane, ethanol and tri-
fluoroacetic acid in the ratio of 50:50:0.2 (v/v/v) respectively; flow rate 0.7 ml/min.; col-
umn temperature 35ꢀC; wavelength 250 nm. The HPLC analysis data is reported in area
% and is not adjusted to weight %. 4-(4-Aminophenyl)morpholin-3-one 4 was purchased
from Taizhou World Pharm & Chem Co., Ltd.
Ethyl N-[4[(3-oxo-4-morpholinyl)phenyl]carbamate (9)
4-(4-Aminophenyl)morpholin-3-one (1.23 kg, 6.40 mol) and K2CO3 (1.07 kg, 7.74 mol)
were suspended in 6.75 L toluene and 2.05 L water at 0–5ꢀC. To the stirred suspension
was slowly added a solution of ethyl chloroformate (0.91 kg, 8.39 mol) in 2.7 L toluene
at the same temperature, then stirring was continued for 3 hr at room temperature. Subse-
quently, to the mixture was added 6.75 L water and it was stirred for 30 min. The precipi-
tate was collected and washed with 1.5 L water. The crude solid was slurried with ethyl
acetate (6.75 L) for 2 hr, collected and dried under vacuum to give 9 as a white solid
(1.49 kg, 88%), mp. 190.3–193.1ꢀC, with 99.2% purity by HPLC.
1H NMR (500 MHz, DMSO) d: 1.24 (t, 3H, J D 7.0 Hz), 3.66 (t, 2H, J D 5.0 Hz),
3.94 (t, 2H, J D 5.0 Hz), 4.10–4.16 (m, 2H), 4.16 (s, 2H), 7.26 (d, 1H, J D 9.0 Hz), 7.46
(d, 2H, J D 8.5 Hz), 9.70 (s, 1H); 13C NMR (125 MHz, DMSO) d: 14.96, 49.61, 60.65,
63.96, 68.19, 118.86, 126.43, 136.46, 137.99, 154.04, 166.36. MS m/z 264.05 [M]C.

174
Xu et al.
(S)-1-chloro-3-[(4-chloro-E-benzylidene)-amino]-propan-2-ol (10)
Compound 10 was synthesized from (S)-epichlorohydrin according to the reported proce-
dure with minor modification.22 To a solution of p-chlorobenzaldehyde (1.48 kg,
10.53 mol) in 6.0 L methanol was added 1.03 L aq. ammonia (28 wt%, 15.44 mol) in
one portion, the resulting mixture was stirred for 20 min at room temperature then (S)-
epichlorohydrin (986.0 g, 15.27 mol) was charged in single portion. The reaction mixture
was stirred for 12 hr then heated to 40 ꢀC and stirred for 2 hr. After cooling to room tem-
perature, 9.0 L water was added and methanol was evaporated under vacuum below
45ꢀC. The precipitate was filtered and slurried with 5.0 L petroleum ether. The solid was
filtered and then dissolved in 5.0 L dichloromethane. The organic phase was separated
and dried with anhydrous Na2SO4. The resultant filtrate containing compound 10 was
used directly for the preparation of 3¢HCl without isolation.
1H NMR (500 MHz, DMSO) d: 3.57–3.62 (m, 2H), 3.70–3.73 (m, 2H), 3.91–3.97
(m, 1H), 5.28 (d, 1H, J D 5.0 Hz), 7.51 (d, 2H, J D 8.5 Hz), 7.77 (d, 2H, J D 8.5 Hz),
8.33 (s, 1H); 13C NMR (125 MHz, DMSO) d: 48.49, 64.08, 70.46, 129.21, 130.06,
135.34, 135.72, 161.81. MS m/z 231.90 [M]C. mp. 70–72.1ꢀC (lit.25 70–71ꢀC).
4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one
hydrochloride (3¢HCl)
To a suspension of 9 (1.43 kg, 5.41 mol) in 2.25 L CH2Cl2 was added lithium t-butoxide
(1.17 kg, 14.62 mol) at 5¡10ꢀC in three portions. After being stirred for 30 min at room
temperature, the above solution containing compound 10 (»8.11 mol) was added over
30 min. The resulting solution was heated to reflux for 12 hr and then cooled to room
temperature, 16.4 L ethanol was added and the pH of the solution was adjusted to 1.0–2.0
using concentrated HCl (1.6 L). The reaction mixture was stirred for 1.5 hr at room tem-
perature and the resultant solid was filtered and washed with ethanol (1.6 £ 2 L). The fil-
trate was stored for the reuse of p-chlorobenzaldehyde. The wet solid was charged into
ethanol (11.0 L), heated to reflux, and stirred for 30 min. The resultant mixture was
cooled to 25¡30ꢀC and stirred for 60 min. The product was filtered, washed with ethanol
(1.1 £ 2 L), and dried at 45ꢀC under reduced pressure (400 mmHg) to afford 1.45 Kg
26
(81.8%) of 3¢HCl as an off-white solid, mp. > 250ꢀC (lit. 210–220ꢀC), with 99.4%
purity by HPLC.
1H NMR (500 MHz, DMSO) d: 3.18–3.23 (m, 2H), 3.71 (t, 2H, J D 5.0 Hz), 3.92
(dd, 1H, J1 D 6.5 Hz, J2 D 9.0 Hz), 3.97 (t, 2H, J D 5.0 Hz), 4.19–4.22 (m, 3H), 4.95–
5.00 (m, 1H), 7.42 (d, 2H, J D 9.0 Hz), 7.56 (d, 2H, J D 9.0 Hz), 8.41 (s, 3H); 13C NMR
(125 MHz, DMSO) d: 41.98, 47.73, 49.48, 63.95, 68.21, 70.04, 119.01, 126.43, 136.78,
137.72, 154.10, 166.46. MS m/z 291 [M-HCl]C.
To the filtrate containing p-chlorobenzaldehyde was added 25 L water, the organic
phase was separated and washed with water (2.5 £ 2 L). After drying (Na2SO4) and evap-
oration of the solvent, the residue was distilled under reduced pressure to give 0.77 kg of
p-chlorobenzaldehyde (92–94ꢀC/10 torr), which could be reused for the synthesis of com-
pound 10.
5-Chlorothiophene-2-carbonyl chloride (8)
5-Chlorothiophene-2-carboxylic acid (0.75 kg, 4.61 mol) was suspended in 2.6 L toluene
and heated to 80ꢀC. Thionyl chloride (640 mL, 8.81 mol) was added dropwise over a

Improved Synthesis of Rivaroxaban
175
period of 20 min, and the reaction mixture was heated to 120ꢀC and stirred for 2 hr at the
same temperature. The reaction was monitored by TLC (charged one drop of reaction
solution into 1 mL methanol) until gas evolution ceases. After removal of the excess thi-
onyl chloride and toluene by evaporation under vacuum, the residue was dissolved in tol-
uene (1.5 L) for the next step.
Rivaroxaban (1). 3¢HCl
(1.40 kg, 4.27 mol) was dissolved in 4.85 L water and filtered, to the filtrate was added
6.0 L toluene and Na2CO3 (0.56 kg, 5.28 mol) at room temperature. The mixture was
cooled to 8 to 12ꢀC, the above solution of 9 in toluene was then added, and the reaction
mixture was stirred for 2 hr at room temperature. After completion of reaction, 2.5 L ace-
tone was added and the precipitated solid was filtered and washed with 2 mol/L aq. HCl
(1.5 L). The wet solid was dried at 70ꢀC under reduced pressure (400 mmHg) to afford
1.76 kg of the crude product 1 with 99.0% purity by HPLC. The crude product was
charged into acetic acid (7.8 L) and heated to reflux for 15 min. The clear solution was
cooled to 15ꢀC and stirred for 2 hr, and the precipitated solid was filtered and washed
with 1.5 L acetone. The wet solid was dried at 70ꢀC under reduced pressure (400 mmHg)
to furnish 1.49 kg (80.0%) of the final product, mp. 228.9–230.1ꢀC (lit.2 232–233ꢀC,
lit.25 227.8–228.5ꢀC), with 99.91% chemical purity and 99.93 chiral purity by chiral
HPLC analysis. 1H NMR (500 MHz, DMSO) d: 3.61 (t, 2H, J D 5.5 Hz), 3.71 (t, 2H, J D
5.5 Hz,), 3.86 (dd, 1H, J1 D 6.0 Hz, J2 D 9.0 Hz), 3.97 (t, 2H, J D 4.5 Hz), 4.20 (t, 3H, J
D 6.5 Hz), 4.83–4.86 (m, 1H), 7.20 (d, 1H J D 4.0 Hz), 7.41 (d, 2H, J D 8.5 Hz), 7.56 (d,
2H, J D 9.0 Hz), 7.69 (d, 1H, J D 4.0 Hz), 8.97 (t, 1H, J D 5.5 Hz); 13C NMR
(125 MHz, DMSO) d: 42.69, 47.92, 49.49, 63.95, 68.20, 71.80, 118.83, 126.41, 128.61,
128.92, 133.73, 136.96, 137.56, 138.93, 154.57, 161.28, 166.43. MS m/z 436.0 [MCH]C.
Isolation of Impurities C and D. The enriched mother liquor (12 ml) from two-fold
recrystallization of Rivaroxaban was further purified on silica gel 60H (150 g), using a
gradient elution system of ethyl acetate-methanol (40:1, 30:1, 25:1, 20:1, 15:1, 10:1, 8:1
volume ratio). The fractions 5–10 were subjected repeatedly to silica gel flash chromatog-
raphy with ethyl acetate-methanol (40:1) as solvent to yield impurity C. The fractions 20–
24 were also subjected repeatedly to silica gel flash chromatography with ethyl acetate-
methanol (10:1) as solvent to yield impurity D.
1
Impurity C: mp. 232.3–233.9ꢀC; H NMR (500 MHz, DMSO): d 3.61 (t, 3H, J D
6.0 Hz), 3.78–3.90 (m, 3H), 4.10 (t, 1H, J D 5.0 Hz), 4.19 (t, 1H, J D 9.0 Hz), 4.36 (d,
1H, J D 2.0 Hz), 4.81–4.86 (m, 1H), 5.22 (d, 1H, J D 6.5 Hz), 5.69 (d, 1H, J D 6.5 Hz),
7.24 (d, 1H, J D 4.0 Hz), 7.37–7.41 (m, 4H), 7.45 (d, 2H, J D 8.5 Hz), 7.57 (d, 2H, J D
9.0 Hz), 7.69 (d, 1H, J D 4.0 Hz), 8.97 (t, 1H, J D 5.5 Hz); 13C NMR (125 MHz,
DMSO): d 42.62, 47.89, 49.78, 62.93, 71.71, 72.61, 81.23, 118.76, 126.25, 127.97,
128.50, 128.75, 128.84, 131.60, 133.60, 136.82, 138.85, 142.06, 154.49, 161.21, 167.13.
MS m/z 598.02 [MCNa]C.
Anal. Calcd. for C26H23Cl2N3O6S: C, 54.17; H, 4.02; N, 7.29. Found: C, 54.08; H,
4.09; N, 7.14.
Impurity D: mp. > 250ꢀC; 1H NMR (500 MHz, DMSO): d 3.69 (d, 4H, J D 4.5 Hz),
3.96 (t, 4H, J D 4.5 Hz), 4.18 (s, 4H), 7.28 (d, 4H, J D 8.5 Hz), 7.47 (d, 4H, J D 9.0 Hz),
8.80 (s, 2H); 13C NMR (125 MHz, DMSO): d 49.64, 63.98, 68.20, 118.90, 126.51,
136.07, 138.42, 152.98, 166.37. MS m/z 411.16 [MCH] C.
Synthesis of Impurities A, B and D. Impurities A and B were synthesized from the
desired thiophenecarbonyl chloride with 3¢HCl according to the procedure described for 1.

176
Xu et al.
1
Impurity A: mp. 194.3–197.7ꢀC; H NMR (500 MHz, DMSO): d 3.60 (t, 2H, J D
5.5 Hz), 3.70 (t, 2H, J D 5.0 Hz), 3.87 (dd, 2H, J1 D 4.0 Hz, J2 D 9.0 Hz), 3.96 (t, 2H,
J D 4.5 Hz), 4.19 (t, 3H, J D 8.0 Hz), 4.82–4.87 (m, 1H), 7.15 (dd, 1H, J1 D 4.0 Hz,
J2 D 5.0 Hz), 7.40 (d, 2H, J D 9.0 Hz), 7.55 (d, 2H, J D 9.0 Hz), 7.76–7.79 (m, 2H), 8.87
(t, 1H, J D 6.0 Hz); 13C NMR (125 MHz, DMSO): d 42.68, 47.95, 49.49, 63.96, 68.21,
71.85, 118.83, 126.44, 128.44, 128.99, 131.61, 136.99, 137.54, 139.81, 154.62, 162.27,
166.44. MS m/z 402.0 [MCH]C.
1
Impurity B: mp. 202.3–205.2ꢀC; H NMR (500 MHz, DMSO): d 3.62 (t, 2H, J D
5.5 Hz), 3.71 (t, 2H, J D 5.0 Hz), 3.83 (dd, 1H, J1 D 6.5 Hz, J2 D 9.0 Hz), 3.96 (t, 2H,
J D 4.5 Hz), 4.16–4.20 (m, 3H), 4.81–4.86 (m, 1H), 7.40 (d, 2H, J D 9.0 Hz), 7.55 (d,
2H, J D 9.0 Hz), 7.86 (s, 1H), 9.07 (t, 1H, J D 6.0 Hz); 13C NMR (125 MHz, DMSO): d
42.77, 47.89, 49.50, 63.97, 68.22, 71.76, 118.81, 123.80, 126.43, 128.26, 129.06, 136.97,
137.16, 137.56, 154.56, 160.45, 166.46. MS m/z 470.0 [MCH]C.
Synthesis of 1,3-bis[4-(3-oxomorpholin-4-yl)phenyl]urea (impurity D). To a solu-
tion of 4-(4-aminophenyl)morpholin-3-one (4.04 g, 21 mmol) in 20 mL DMF were
added triethylamine (1.01g, 10 mmol) and CDI (1.62g, 10 mmol) at room temperature
under nitrogen atmosphere. The reaction mixture was stirred at same temperature over-
night before poured into water. The precipitant was filtered, washed with water and then
washed with acetone. The resultant solid was dried at 60ꢀC for 2 hr to get the title com-
1
pound (2.65g, 64.6%), an off-white powder. The H NMR and mp. are in accordance
with impurity D separated from rivaroxaban.
Acknowledgments
This work was supported by Changsha Administration of Science & Technology
(k1508012-11).
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