An Improved, Scalable and Impurity-Free Process for Lixivaptan

Article abstract of DOI:10.1002/jhet.2176

An optimized synthetic method in high efficiency has been developed for the synthesis of lixivaptan from 2-nitrobenzyl bromide and pyrrole-2-carboxaldehyde. The byproducts among this procedure and an unknown impurity in crude product were investigated. The byproducts were speculated by ¹H NMR or MS. The unknown impurity was characterized by ¹H NMR, ¹³C NMR, and HRMS, confirming the structures as N-[3-chloro-4-(5H-pyrrolo[2,1-c][1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl]-N-(5-fluoro-2-methylbenzoyl)-5-fluoro-2-methylbenzamide. Afterwards, the impurity was synthesized to make comparisons. The target product lixivaptan was obtained with 47.6% overall yield and 99.93% purity. This cost-effective and environmentally friendly process is suitable for scale-up production.

Full text of DOI:10.1002/jhet.2176

Month 2014
An Improved, Scalable and Impurity-Free Process for Lixivaptan
c
c
b
c
d
Shuai Mu,a,c Duan Niu, Ying Liu, Dashuai Zhang, Dengke Liu, and Changxiao Liu
*
aSchool of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
bGraduate School of Tianjin Medical University, Tianjin 300070, China
cTianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research
Tianjin 300193, China
dState Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research,
Tianjin 300193, China
*
E-mail: liudk@tjipr.com
Received October 2, 2013
DOI 10.1002/jhet.2176
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
An optimized synthetic method in high efficiency has been developed for the synthesis of lixivaptan from
2-nitrobenzyl bromide and pyrrole-2-carboxaldehyde. The byproducts among this procedure and an unknown im-
purity in crude product were investigated. The byproducts were speculated by 1H NMR or MS. The unknown im-
purity was characterized by 1H NMR, 13C NMR, and HRMS, confirming the structures as N-[3-chloro-4-(5H-pyrrolo
[2,1-c][1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl]-N-(5-fluoro-2-methylbenzoyl)-5-fluoro-2-methylbenzamide.
Afterwards, the impurity was synthesized to make comparisons. The target product lixivaptan was obtained with
47.6% overall yield and 99.93% purity. This cost-effective and environmentally friendly process is suitable
for scale-up production.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
suitability, an improved synthetic route based on procedure
A with an overall yield of 47.6% and purity of 99.93% was
developed. The byproducts among this procedure and an
impurity observed in the crude lixivaptan product were also
investigated.
Lixivaptan is an oral, nonpeptide vasopressin V2 receptor
antagonist applied in the treatment of hyponatremia [1–6].
Recent reports demonstrated that it might have benefits to
patients with congestive heart failure [7–10], cirrhosis [11],
and syndrome of inappropriate antidiuretic hormone secretion
[12,13]. It is chemically known as N-[3-chloro-4-(5H-pyrrolo
[2,1-c][1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl]-
5-fluoro-2-methylbenzamide, which is represented by
chemical formula in Figure 1.
The reported two procedures (A and B) for synthesizing
lixivaptan were shown in Scheme 1 [14–17]. Procedure A
suffered from several drawbacks including the following:
(i) use of pyrophoric reagents such as sodium hydride
[15,18] resulted in the process industrially unattractive; (ii)
poor volume efficiency; and (iii) partial dechlorination when
Pd/C was used to catalyze the reduction of nitro [14].
Procedure B seemed to be more efficient than procedure A;
however, it failed to obtain the desired purity of final product
after successive recrystallization in different solvents such as
methanol, ethyl acetate, chloroform–methanol, and hexane-
ethyl acetate in our process development research. Upon
the consideration for the commercial availability of the raw
materials, the quality of the final product and the scale-up
RESULTS AND DISCUSSION
The detailed modifications on procedure A were in
reaction conditions a, b, and c, illuminated in Scheme 1.
Our data indicated that the improved synthetic method
was more efficient and scalable than conventional proce-
dure A. The effects of variant reaction conditions in this
modified procedure A on volume efficiency, yield, and
purity were listed in Table 1.
In conventional procedure A, sodium hydride was used
in the synthesis of 5. Sodium hydride may ignite in air,
especially upon contact with water to release hydrogen,
which is also flammable, so extensively dried solvent was
employed to ensure the safe operation. Moreover, the
production yield and purity from conventional procedure
were not satisfied for scale-up production. The effects of
different bases were considered in this study for the
improvement of conventional procedure (Table 2). It was
found that the usage of anhydrous potassium carbonate
© 2014 HeteroCorporation

S. Mu, D. Niu, Y. Liu, D. Zhang, D. Liu, and C. Liu
Vol 000
desired solubility in ethyl acetate of product 6, the substrate
does not need to be fully dissolved fortunately. The amount
of solvent can be further reduced to 3 mL/g. The increase
of the temperature slowed the absorption of hydrogen in
turn, which extended the reaction time more than 24 h. A
scalable method for the reduction and cyclization step was
developed to overcome these disadvantages. In hydrogen at-
mosphere under a relatively higher pressure (0.1 ~ 0.2 MPa)
and temperature (60°C), 6 was prepared from 5 with a yield
of 90% and a purity of 99%.
Stannous chloride was industrially unattractive for the
reduction of nitro. However, partial dechlorination
(3 ~ 5%) was observed when Pd/C―H2 in refluxing etha-
nol was introduced during preparation of 9. In addition,
the poor solubility of 9 in the solvent usually employed
in the catalytic hydrogenation (such as methanol, ethanol,
ethyl acetate, and tetrahydrofuran) suggested that it was
difficult to separate the product from the reaction mixture.
Finally, 9 was acquired by the reduction of 8 with Pd/
C―H2 in N,N-dimethylformamide at no more than 40°C,
which reduced dechlorination (<2%), increased solubility,
thereby improving the yield and purity of the product.
Figure 1. Chemical structure of lixivaptan.
instead of sodium hydride made the reaction controllable,
with a total yield of more than 90%. The intermediate 5
could be used directly to the next reduction and cyclization
step without further purification. The influence of different
solvents was evaluated among tetrahydrofuran, dioxane, N,
N-dimethylformamide, acetone, acetonitrile, and toluene;
however, no significant difference in yield and product
purity was observed.
Compound 6 was synthesized from 5 using a one-pot
method. Possible reaction pathway was shown in
Scheme 2. At room temperature, over 20 mL/g of ethyl
acetate was required to dissolve compound 5, but 5
changed more soluble (~5 mL ethyl acetate) at 60°C. The
Scheme 1. Synthetic route for lixivaptan.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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An Improved, Scalable and Impurity-Free Process for Lixivaptan
Table 1
Comparisons of solvent volume, yield, and purity.
Conventional procedure A
Solvent volume (mL/g) Yield (%)
23 (DMF)
Improved procedure A
Reaction
conditions
Purityb (%)
Solvent volume (mL/g)
Yield (%)
Purity (%)
a
b
c
95a
66
97.0
99.0
96.2
6 (THF)
92
93
87
99.5
99.0
98.8
26 (ethyl acetate and ethanol 1:1)
34 (ethanol)
3 (ethyl acetate)
3 (DMF)
—
aReported in patents [17]. Experimental data is 60–70%.
bNo purity data was reported by literatures; experimental data was listed instead.
Table 2
Effects of different bases.a
Base
NaH
TEA
K2CO3
KOH
NaOH
Temperature (°C)
Reaction time (h)b
Yield (%)
0
2
63
97.0
65
4
88
99.3
65
5
92
99.5
r.t.
3
70
r.t.
3
76
99.0
Purity (%)
97.8
aThe reactions were conducted in THF.
bMonitored by TLC every 30 min. Postprocessing time was not included.
Scheme 2. Possible pathway of the reaction from 5 to 6.
Except the dechlorination byproduct 9a, another two
byproducts 9b and 9c were also observed (Scheme 3) in
the reaction process. It is because nitro reductions are
known to proceed through various intermediates such as
nitroso and hydroxylamine [19–21]. Compound 9b was
(5H-pyrrolo[2,1-c][1,4]benzodiazepine-10(11H)-ylcarbonyl)
phenyl]-N-(5-fluoro-2-methylbenzoyl)-5-fluoro-2-methylbe-
nzamide. Possible mechanism for the formation of the impu-
rity was shown in Scheme 4. Theoretically, it is difficult to
prepare imides from amides because of the strong electron-
withdrawing effect from the carbonyl group. However,
lixivaptan can be completely transformed into the impurity
by the introduction of DMAP and increase of temperature.
1
characterized by H NMR; however, 9c was characterized
simply by MS because of the low level in crude intermedi-
ate 9. Extending reaction time can effectively reduce the
levels of 9b and 9c. Meanwhile, these byproducts can
easily be removed by washing with hot ethanol.
1
Comparison of the H NMR, 13C NMR, HRMS, and the
HPLC spectrum of the impurity and the synthesized sample
further verified the structure of the impurity.
The optimum reaction conditions were considered to
eliminate the imide impurity. The introduction of the impu-
rity was probably due to the excess of 10. Temperature is
another important factor for the generation of the impurity.
During the synthesis investigation, an impurity was
observed in crude lixivaptan product. Then, the impurity
was isolated from crude product via silica gel chromatography
1
successfully and characterized by H NMR, 13C NMR, and
HRMS, which confirmed the structure as N-[3-chloro-4-
Scheme 3. Byproducts observed in the reaction from 5 to 6.
Journal of Heterocyclic Chemistry
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S. Mu, D. Niu, Y. Liu, D. Zhang, D. Liu, and C. Liu
Vol 000
Scheme 4. Synthesis of the impurity.
EXPERIMENTAL
Scheme 5. Formation of the predictable impurity from the byproduct 9a.
Reagents and solvents were obtained from commercial
suppliers. All reactions were monitored by thin layer chromatog-
raphy. Silica gel chromatography was conducted by Teledyne
Isco COMBIFLASH Rf200 Purification System (petroleum ether
and ethyl acetate, gradient elution); chromatographic analysis was
performed with an Agilent 1260 equipped with a Grace C18
1
column (5 μ, 250 mm × 4.6 mm, Lot No. 55/182). H NMR and
13C NMR spectra were recorded on BRUKER AV400 NMR.
HRMS was detected on VG ZAB-HS. Melting points were
observed on a YRT-3 Melting Point Tester (uncorrected).
1-(2-Nitrobenzyl)-2-pyrrolecarboxaldehyde (5). To a mixture
of 2-nitrobenzyl bromide (455g, 2.1 mol) and pyrrole-2-car
boxaldehyde (200g, 2.1mol) in tetrahydrofuran (1200mL) was
added anhydrous potassium carbonate (440 g, 3.2 mol). Then, the
mixture was heated to reflux and stirred for about 5 h. Then, the
reaction mixture was poured into 2400 mL of water and stirred for
an additional 0.5 h. Potassium carbonate was completely dissolved
in water and yellow solid precipitated. After filtration, the resulting
residue was vacuum dried to give desired product 5 as a light yellow
solid (445 g, yield 92%), mp 135–137°C. 1H NMR (400 MHz,
DMSO-d6) δ: 5.85 (s, 2H), 6.39 (dd, J1 = 3.6 Hz, J2 = 2.4 Hz, 1H),
6.44 (d, J= 7.6 Hz, 1H), 7.17 (dd, J1 =4.0Hz, J2 =1.6Hz, 1H), 7.45
(s, 1H), 7.52–7.54 (m, 1H), 7.61–7.63 (m, 1H), 8.11 (dd,
J1 =8.0Hz, J2 =1.2Hz, 1H), 9.442 (d, J=0.80 Hz, 1H).
10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (6).
Compounds 5 (400g, 1.7mol), 10% Pd/C (20g), and ethyl acetate
(1200 mL) were added into a 5-L high pressure reactor. At
hydrogen atmosphere, the mixture was heated to 60°C, and the
pressure was maintained at 0.1–0.2 MPa for 4 h. After the
system was cooled to ambient temperature, the reaction mixture
was filtrated to give colorless solution. Three quarters of the
solvent was evaporated off under reduced pressure and white
crystal precipitated. The desired product was obtained as
white crystal (297 g, yield 93%), mp 152–154°C. 1H NMR
(400 MHz, DMSO-d6) δ: 4.33 (d, J = 4.8 Hz, 2H), 5.18 (s,
2H), 5.82 (t, J = 3.2 Hz, 1H), 5.86 (q, J = 1.6 Hz, 1H), 6.07
(t, J = 4.8 Hz, 1H), 6.38–6.46 (m, 2H), 6.72–6.73 (m, 1H),
6.87–6.94 (m, 2H).
Finally, the product free from the impurity was prepared
when the amount of 10 was added at 1 eq of 9, and the
reaction temperature was less than 0°C.
Another possible impurity 2a (Scheme 5) was con-
cerned because of the side reaction illustrated in
Scheme 3, even though the impurity 2a was not detected
in the final product. After recrystallization in ethyl acetate
and washed with methanol, the purity of the final product
was 99.93% with a maximum single impurity level no
more than 0.05%.
CONCLUSION
In conclusion, the synthetic process of lixivaptan has been
improved for obtaining satisfied yields and quality by
modification of the reaction conditions. All intermediates
and the final product could be prepared with readily
available, cost-effective, and environmentally friendly
reagents and solvents; those made the method more suitable
for large-scale industrial production than conventional
method. Additionally, the byproducts among this procedure
and an impurity in crude product were investigated. The
byproducts were speculated by 1H NMR or MS. The impu-
rity was separated from the crude-synthesized lixivaptan and
1
characterized by H NMR, 13C NMR, and HRMS, indicat-
2-Chloro-4-nitrobenzoyl chloride (7). N,N-Dimethylformamide
(10 mL) was added into the mixture of 2-chloro-4-nitrobenzoic acid
(322 g, 1.6 mol) and dichloromethane (900 mL) followed
heating to reflux. Thionyl chloride (381 g, 3.2 mol) was added
dropwise into the mixture and stirred for an additional 4 h.
Then, the solution was concentrated in vacuo to afford 2-
chloro-4-nitrobenzoyl chloride (7) as yellow oil, which was
taken on to the next step without purification.
ing the structure as N-[3-chloro-4-(5H-pyrrolo[2,1-c][1,4]
benzodiazepine-10(11H)-ylcarbonyl)phenyl]-N-(5-fluoro-2-
methylbenzoyl)-5-fluoro-2-methylbenzamide (2). Synthesis
of the impurity further verified its structure. Meanwhile,
optimum reaction conditions free from the byproducts and
the impurity were developed.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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An Improved, Scalable and Impurity-Free Process for Lixivaptan
(2-Chloro-4-nitrophenyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-
10(11H)-yl-methanone (8). Triethylamine (230 g, 2.3 mol) was
added into a solution of 6 (280 g, 1.5 mol) in dichloromethane
(1000 mL). After the mixture was cooled to 0°C, 7 dissolved in
dichloromethane (500 mL) was added dropwise into the mixture and
stirred for 5 h. Then, the mixture was washed successively with
1 mol/L hydrochloric acid and water. The organic layer was dried
over anhydrous magnesium sulfate and evaporated to give brown
oil. Methanol (1000 mL) was added to the oil and yellow solid
precipitated. The intermediate 8 was afforded by filtration as
Isolation of the impurity (2). The recrystallization mother
liquor of lixivaptan was concentrated and separated by silica gel
1
chromatography to afford the impurity, mp 203–207°C. H NMR
(400 MHz, DMSO-d6) δ: 2.23 (s, 6H), 5.22 (br, 4H), 5.89 (t,
J= 3.0 Hz, 1H), 5.99 (s, 1H), 6.81 (s, 1H), 6.85-6.92 (m, 2H), 7.08–
7.19 (m, 5H), 7.28–7.35 (m, 2H), 7.56–7.59 (m, 2H), 7.71 (s, 1H).
13C NMR (DMSO-d6, 400 MHz) δ: 18.4, 45.0, 49.3, 106.8, 108.6,
113.9, 114.1, 117.5, 117.7, 122.2, 124.8, 127.4, 127.9, 128.1,
128.3, 128.4, 129.0, 129.7, 130.2, 132.4, 132.5, 132.5, 132.6,
135.3, 135.9, 136.3, 136.3, 139.4, 158.4, 160.8, 166.1, 170.4.
HRMS (ESI), calcd: C35H26ClF2N3O3 [M+H]+ m/z: 610.1704,
found: 610.1699. HPLC retention time: 12.06 min (methanol:
H2O=4:1, flow rate 0.5 mL/min).
1
yellow powder (470 g, yield 84%), mp 135–138°C. H NMR
(400 MHz, DMSO-d6) δ: 5.24 (br, 4H), 5.90 (t, J = 3.0 Hz,
1H), 6.01 (s, 1H), 6.83 (s, 1H), 7.03–7.08 (m, 2H), 7.11–7.15
(m, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.71 (s, 1H), 8.01 (d,
J = 8.0 Hz, 1H), 8.21 (s, 1H).
N-[3-Chloro-4-(5H-pyrrolo[2,1-c][1,4]benzodiazepine-10(11H)-
ylcarbonyl)phenyl]-N-(5-fluoro-2-methylbenzoyl)-5-fluoro-2-
methylbenzamide (2). Compound 7 (2.2 g, 12.7 mmol) was added
to the mixture of lixivaptan (5 g, 10.6 mmol) in dichloromethane
(30 mL) with triethylamine (1.6 g, 15.8 mmol) and DMAP (0.25 g).
The mixture was refluxed for 4 h, and the reaction solution was
washed successively by 1 mol/L hydrochloric acid and water.
The organic phase was dried over anhydrous magnesium sulfate
and concentrated. The residue was purified by recrystallization
(petroleum ether/ethyl acetate = 50/50, v/v, 20 mL) to give
compound 2 as yellow solid (3.9 g, 60%), mp 203–207°C. 1H
NMR (DMSO-d6, 400 MHz) δ: 2.23 (s, 6H), 5.25 (br, 4H), 5.89
(s, 1H), 5.99 (s, 1H), 6.81 (s, 1H), 6.85–6.92 (m, 2H), 7.08–7.19
(m, 5H), 7.25–7.35 (m, 2H), 7.54–7.63 (m, 2H), 7.71 (s, 1H). 13C
NMR (400 MHz, DMSO-d6) δ: 18.4, 45.0, 49.3, 106.8, 108.6,
113.9, 114.1, 117.4, 117.6, 122.1, 124.8, 127.4, 127.9, 128.1,
128.3, 128.4, 128.9, 129.7, 130.2, 132.4, 132.4, 132.5, 132.6,
135.3, 135.9, 136.2, 136.3, 139.4, 158.4, 160.8, 166.1, 170.4.
HRMS (ESI), calcd: C35H26ClF2N3O3 [M+H]+ m/z: 610.1704,
found: 610.1699. HPLC retention time: 12.04 min (methanol:
H2O=4:1, flow rate 0.5 mL/min).
(4-Amino-2-chlorophenyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-
10(11H)-yl-methanone (9). The mixture of 8 (450 g, 1.2 mol)
and 5% Pd/C (23 g) in N,N-dimethylformamide (1400 mL) was
stirred at 35 ~ 40°C for 6 h under hydrogen atmosphere. Then,
the insoluble solid was removed, and the resulting filtrate was
poured into water (5000 mL) and white solid precipitated. The
crude solid was stirred in refluxing ethanol for 0.5 h. After
filtration and drying, compound 9 was obtained as white
powder (360 g, yield 87%), mp 210–212°C. 1H NMR
(400 MHz, DMSO-d6) δ: 4.98 (s, 2H), 5.20 (s, 2H), 5.54
(s, 1H), 5.88–5.91 (m, 2H), 6.26 (s, 1H), 6.46 (s, 1H),
6.78s, 1H), 6.88 (d, J = 7.2 Hz, 1H), 6.99 (s, 1H), 7.13 (s, 2H),
7.38 (d, J = 4.4 Hz, 2H).
Separation of the byproducts (9a, 9b, and 9c). The crude solid of
9 was separated by preparative HPLC to afford the byproducts. 9a: 1H
NMR (400 MHz, DMSO-d6) δ: 4.98 (br s, 2H), 5.23 (s, 2H), 5.49 (s,
2H), 5.91 (s, 2H), 6.30 (d, J= 8.4 Hz, 2H), 6.79–6.85 (m, 2H), 6.95
(d, J = 8.4 Hz, 2H), 7.11–7.19 (m, 2H), 7.46–7.48 (d,
1
J = 6.4 Hz, 2H). 9b: H NMR (400 MHz, DMSO-d6) δ: 5.03–
5.23 (m, 4H), 5.89–5.95 (m, 2H), 6.50 (s, 1H), 6.71 (s, 1H),
6.79 (s, 1H), 6.99–7.11 (m, 4H), 7.39 (s, 1H), 8.51 (s, 1H),
8.61 (s, 1H). 9c: MS (ESI), [M+H]+ m/z: 352.3.
5-Fluoro-2-methylbenzoyl chloride (10). Similar to the preparation of
7, a mixture of 5-fluoro-2-methylbenzoic acid (200 g, 1.3 mol),
dichloromethane (600 mL), and N,N-dimethylformamide (10 mL) was
added thionyl chloride (310 g, 2.6 mol) and heated to reflux
for 4 h. The solution was concentrated to afford 5-fluoro-2-me
thylbenzoyl chloride (7) as chartreuse oil, which was taken on
to the next step without purification.
Acknowledgments. This project was supported by the National
Basic Research Program of China (973 Program, granted
nos. 2010CB735602 and 2012CB724002) and the National
Major Scientific and Technological Special Project for
“Significant New Drugs Development” (nos. 2011ZX09401-009
and 2013ZX09102014).
Lixivaptan (1).
To a mixture of 9 (360 g, 1.1 mol) in dic
hloromethane (1500 mL), triethylamine (160 g, 1.6 mol) was added.
Thereafter, 10 (184 g, 1.1 mol) dissolved in 400 mL of dichl
oromethane was added dropwise into the reaction mixture followed
stirring for 5 h under 0°C. Then, the mixture was washed
successively with 1 mol/L hydrochloric acid and water. The
organic layer was dried over anhydrous magnesium sulfate
and concentrated to a residue as brown solid. Methanol
(500 mL) was added to the residue and heated to reflux; then,
the mixture was filtrated to give crude product, which was
purified by recrystallization in ethyl acetate (1000 mL) after 2 h
stirring. Finally, the sample was washed with methanol (500mL)
to give final product as white powder (355, yield 70%, purity
99.93%), mp 169–172°C. 1H NMR (400 MHz, DMSO-d6) δ: 2.30
(s, 3H), 5.27 (br, 4H), 5.91 (s, 1H), 5.99 (s, 1H), 6.82 (s, 1H),
7.05–7.14 (m, 3H), 7.23 (t, J = 8.4Hz, 1H), 7.33 (d, J = 8.4Hz,
3H), 7.39–7.51 (m, 3H), 7.84 (s, 1H), 10.50 (s, 1H). HRMS (ESI),
calcd: C27H21ClFN3O2 [M+H]+ m/z: 474.1379, found: 474.1385.
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