An approach to the anticoagulant agent rivaroxaban via an isocyanate-oxirane cycloaddition promoted by MgI2.etherate

Article abstract of DOI:10.3184/174751911X13098778358582

A convergent and efficient synthesis of anticoagulant rivaroxaban was developed using the cycloaddition of commercially available (R)-epichlorohydrin with 4-(morpholin-3-one)phenyl isocyanate catalysed by MgI₂ etherate as the key step, in 22% overall yield.

Full text of DOI:10.3184/174751911X13098778358582

400 RESEARCH PAPER
JULY, 400–401
JOURNAL OF CHEMICAL RESEARCH 2011
An approach to the anticoagulant agent rivaroxaban via an
isocyanate-oxirane cycloaddition promoted by MgI2.etherate
Chao Lia, Yingshuai Liua, Yongjun Zhangb and Xingxian Zhanga*
a College of Pharmaceutical Sciences, Zhejiang University ofTechnology, Hangzhou 310032, P. R. China
bZhejiang Apeloa MedicalTechnology Co., Ltd, Dongyang 322118, P. R. China
A convergent and efficient synthesis of anticoagulant rivaroxaban was developed using the cycloaddition of com-
mercially available (R)-epichlorohydrin with 4-(morpholin-3-one)phenyl isocyanate catalysed by MgI2 etherate as the
key step, in 22% overall yield.
Keywords: (R)-epichlorohydrin, isocyanate, MgI2.etherate, rivaroxaban
Despite recent progress in antithrombotic therapy, there is still
a medicial need for safe and orally available anticoagulants.1
The serine protease factor Xa (Fxa) plays a crucial role in the
coagulation process.2 The coagulation enzyme factor Xa is a
particularly promising target. Rivaroxaban, a member of a new
class of potent Fxa inhibitors, is a novel oxazolidinone deriva-
tive and provides a simple, fixed-dose regimen for treating
acute deep-vein thrombosis (DVT), without the need for labo-
ratory monitoring.3 It has been used in the prophylaxis and
treatment of thromboembolic diseases.4 Rivaroxaban was
introduced into the market which led to the need for a high-
yielding, economical and environmentally sound process for
its production.
The general synthetic method for rivaroxaban derived
from a (5S)-5-phthalimido-protected oxazolidinone, as the key
intermediate, which was obtained via the reaction of benzyl
[4-(3-oxomorpholino)phenyl]carbamate with commercially
available (R)-(-)-glycidol butyrate in the presence of butyl-
lithium, was firstly developed by Manninen.5 Opening of
N-glycidylphthalimide with 4-(4-aminophenyl) morpholin-
3-one and then ring closure with N,N′-carbonyldiimidazole
(CDI) also provided the (5S)-5-phthalimido-protected oxa-
zolidinone, which was subjected to deprotection and acylation
to produce rivaroxaban.1 Thomas6 has developed a modified
synthetic method for rivaroxaban via acylation of (2S)-3-
aminopropan-1, 2-diol hydrochloride with 5-chlorothiophene-
2-carbonyl chloride, bromination, subsequent halogen
substitution with 4-(4-aminophenyl)morpholin-3-one and ring
closure with CDI. Another synthetic method via 5-chlorothio-
phene-2-carboxamide and coupling with methyl N-(2R,3-
epoxy-1-propyl)-N-[4-(3-oxomorpholino) phenyl]carbamate,
whichisobtainedfrommethylN-[4-(3-oxomorpholino)phenyl]
carbamate and (R)-epichlorohydrin in the presence of NaH, to
give rivaroxaban upon treatment with n-BuLi was developed.7
In our previous paper,8 we have demonstrated that MgI2.ether-
ate could efficiently promote the cycloaddition of isocyanates
with oxiranes to give 3-aryloxazolidin-2-one derivatives,
which provides easy access to the rivaroxaban key intermedi-
ate 6. On the basis of this protocol we now report a more con-
vergent, practical and rapid synthetic method for preparation
of rivaroxaban.
As shown in Scheme 1, treatment of N-phenylethanolamine
with chloroacetyl chloride in ethanol afforded 4-phenylmor-
pholin-3-one 2. Treatment of compound 2 with concentrated
sulfuric acid and 65% nitric acid provided 4-(4-nitrophenyl)-
morpholin-3-one 3, which was then subjected to hydrogena-
tion.9 The product, 4-(4-aminophenyl)-morpholin-3-one 4,
reacted with bis(trichloromethyl)carbonate (triphosgene, BTC)
to give the aryl isocyanate 5. Cycloaddition of isocyanate 5
with (R)-epichlorohydrin catalysed by 50 mol % MgI2.etherate
in refluxing THF efficiently afforded the desired, enantiopure,
cycloadduct 6 in 78% yield. The oxazolidinone 6 was trans-
formed into azide 7 in 87% yield by treatment of sodium azide.
Azide 7 was subjected to hydrogenation to afford amine 8,
and successive acylation with 5-chlorothiophene-2-carbonyl
chloride provided rivaroxaban 1 in 80% yield over two steps.
In conclusion, we have described a highly-efficient and
gentle method for the preparation of the anticoagulant agent
rivaroxaban using the cycloaddition of (R)-epichlorohydrin
with substituted phenyl isocyanate 5 catalysed by MgI2.
etherate as the key step. Further synthetic application of MgI2.
etherate-catalysed cycloadditions of epoxides with isocyanates
into natural products and drugs is ongoing in our laboratory.
Scheme 1 Reagents and conditions: i, EtOH, 50% NaOH-H2O; ii, 98% H2SO4, 65% HNO3; iii, H2, 5% Pd–C, EtOH, 40°C; iv, BTC,
toluene, reflux; v, (R)-epichloro -hydrin, MgI2.etherate, THF, 65 °C; vi, NaN3, DMF, 85 °C; vii, H2, 5%Pd-C, EtOAc; viii, 5-
chlorothiophene-2-carbonyl chloride, Et3N, CH2Cl2, 0°C.
* Correspondent. E-mail: mhmosslemin@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2011 401
celite, and the solvent was removed to give compound 8 (370 mg) in
91% yield, Rf = 0.14 (CH3OH), as a white solid, m.p. 148.3–149.8°C.
IR (KBr) (νmax /cm−1): 3345, 1724 (C=O), 1660 (C=O), 1524, 1435,
996, 835. δH 2.98 (dd, J = 5.0, 13.5 Hz, 1H), 3.12 (dd, J = 4.0, 13.5 Hz,
1H), 3.76 (t, J = 5.0 Hz, 2H), 3.86–3.89 (m, 1H), 4.03–4.06 (m, 3H),
4.34 (s, 2H), 4.66–4.70 (m, 1H), 7.35 (d, J = 9.0 Hz, 2H), 7.61 (d,
J = 9.0 Hz, 2H).
Experimental
For product purification by flash column chromatography, silica gel
(200–300 mesh) and light petroleum ether (PE, b.p. 60–90 °C) were
used. 1H NMR spectra were taken on a Bruker Avance-500 spectrom-
eter with TMS as an internal standard and CDCl3 as solvent. Reaction
monitoring was accomplished by TLC on silica gel polygram SILG/
UV 254 plates. Melting points were measured on Büchi B-540
apparatus and are uncorrected. FT-IR spectra were recorded on a
Bruker Tensor 27 spectrometer. HRMS were carried out on Waters
GCT Premier GC/TOF instrument. All compounds were identified by
1H NMR and are in good agreement with those reported.
4-(3-Oxomorpholino)phenyl isocyanate (5): To a solution of 4-
(4-aminophenyl)-morpholin-3-one 410(1.68 g, 8.8 mmol) in toluene
(150 mL) was added dropwise a solution of bis(trichloromethyl) car-
bonate (1.63 g, 5.5 mmol) in toluene (30 mL) at room temperature.
The reaction mixture was then refluxed for 4 h. After removal of the
solvent, the residue was distilled under reduced pressure to give the
desired product 5 (1.35 g) in 71% yield. IR (KBr) (νmax/cm−1): 2878,
2333 (N=C=O), 1647 (C=O), 1531, 1468, 1326, 1244, 1124.
(5R)-5-Chloromethyl-3-[4-(3-oxomorpholino)phenyl]oxazolidin-
2-one (6)11: To a stirred solution of freshly prepared MgI2.etherate12
(2.78 mmol) in THF (15 mL) was added dropwise (R)-epichlorohy-
drin (640 mg, 6.9 mmol) followed by addition of the isocyanate 5
(1.20 g, 5.56 mmol) at room temperature under nitrogen. After com-
pletion of the addition, the reaction mixture was allowed to warm to
80 °C and stirred for 4 h. The resulting homogeneous reaction mixture
was quenched with saturated aqueous Na2SO3 solution. Extractive
workup with CH2Cl2 and flash chromatographic purification of the
crude product on silica gel, eluting with ethyl acetate-n-hexane (2:1),
gave compound 6 (721 mg) in 78% yield, Rf = 0.49 (ethyl acetate),
as a yellowish solid. m.p. 148–149.7 °C, IR (KBr) (νmax /cm−1): 2873,
1739 (C=O), 1657 (C=O), 1519, 860, 830. δH 3.71–3.72 (m, 2H), 3.84
(dd, J = 6.0, 9.0 Hz, 1H), 3.93–4.03 (m, 4H), 4.20 (s, 2H), 4.18–4.24
(m, 1H), 5.02 (m, 1H), 7.41 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 9.0 Hz,
2H).
5-Chloro-N-{[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinophenyl]oxazol-
idin-5-yl]methyl} thiophene-2-carboxamide (Rivaroxaban) (1):1 To
a solution of compound 8 (570 mg, 1.8 mmol) in dichloromethane
(10mL) was added triethylamine (360 mg, 3.6 mmol), followed
by addition of 5-chlorothiophene-2-carbonyl chloride (398 mg,
2.2 mmol) at 0 °C. The reaction mixture was stirred for 1 h and
quenched by addition of water. The reaction mixture was extracted
with ethyl acetate, dried and concentrated under reduced pressure.
The crude product was purified by flash chromatography on silica
gel eluting with ethyl acetate to give rivaroxaban 1 (689 mg) in 88%
yield, Rf = 0.30 (ethyl acetate), as a white solid, m.p. 229.3–230.7 °C
(lit.1, 230 °C). [α]D = −37° (c = 0.5, DMSO) [lit.1, [α]D = –38°
(c = 0.2985, DMSO)]. IR (KBr) (νmax /cm−1): 3343, 1724 (C=O), 1649
(C=O), 1523, 1430, 808, 756. δH 3.60–3.62 (m, 2H), 3.71–3.73 (m,
2H), 3.84–3.87 (dd, J = 6.5, 9.5 Hz, 1H), 3.96–3.98 (m, 2H), 4.20 (s,
2H), 4.18–4.21 (m, 1H), 4.83–4.86 (m, 1H), 7.20 (d, J = 4.0 Hz, 1H),
7.41 (d, J = 9.0 Hz, 2H), 7.56 (d, J = 9.0 Hz, 2H), 7.69 (d, J = 4.0 Hz,
1H), 8.99 (t, J = 5.5 Hz, 1H). δC 42.19, 47.43, 49.00, 63.46, 67.71,
71.30, 118.35, 125.92, 128.11, 128.43, 133.24, 136.48, 137.08,
138.43, 154.08, 160.79, 165.95.
20
21
Financial support was provided by the Zhejiang Province
Natural Science Foundation of China (Project Y4100692) and
Zhejiang Apeloa Medical Technology Co., Ltd.
Received 4 March 2011; accepted 9 June2011
Paper 1100605 doi: 10.3184/174751911X13098778358582
Published online: 5 August 2011
(5S)-5-Azidomethyl-3-[4-(3-oxomorpholino)phenyl]oxazolidin-2-
one (7): Sodium azide (312 mg, 4.8 mmol) was added to a solution of
compound 6 (540 mg, 1.59 mmol) in DMF (5 mL) with stirring. The
reaction mixture was allowed to warm to 85 °C and stirred continu-
ously for 12 h. After completion of the reaction (TLC), the mixture
was diluted with ethyl acetate and washed with water. The crude
product was purified by flash chromatography on silica gel eluting
with ethyl acetate-n-hexane (2:1) to give the compound 7 (474 mg) in
87% yield, Rf = 0.49 (ethyl acetate), as a yellowish solid, m.p. 97.5–
99.3 °C. IR (KBr) (νmax /cm−1): 2872, 2101 (N=N=N), 1737 (C=O),
1644, 1516, 1416, 826. EI-MS (m/z): 317 (M+, 36), 289 (33), 245
(100), 244 (65), 219 (89), 145 (77), 118 (66). δH 3.60 (dd, J = 4.0, 13.5
Hz, 1H), 3.72 (dd, J = 4.5, 13.5 Hz, 1H), 3.76 (t, J = 5.0 Hz, 2H),
3.79–3.89 (m, 1H), 4.05 (t, J = 5.0 Hz, 2H), 4.10 (t, J = 9.0 Hz, 1H),
4.35 (s, 2H), 4.78–4.82 (m, 1H), 7.37 (d, J = 9.0 Hz, 2H), 7.60 (d, J =
9.0 Hz, 2H). δC 47.38, 49.66, 53.00, 64.09, 68.53, 70.67, 119.06,
119.09, 126.24, 136.63, 137.30, 153.92, 166.90. EI-HRMS Calcd for
C14H15N5O4: 317.1124. Found: 317.1108.
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