One-Pot Synthesis of Papaverine Hydrochloride and Identification of Impurities

Article abstract of DOI:10.1134/S1070428020070258

Abstract: A one-pot synthesis of papaverine hydrochloride with 99.6% purity was performed using xylene as solvent for the entire process. The critical parameters of each step, as well as the impurities generated, were identified. The overall yield was improved to 63%. The proposed synthetic procedure is suitable for industrial production.

Full text of DOI:10.1134/S1070428020070258

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 7, pp. 1295–1299. © Pleiades Publishing, Ltd., 2020.
One-Pot Synthesis of Papaverine Hydrochloride
and Identification of Impurities
Wen-Shuai Yua,b, Ze-Nong Wub,c, Zeng-Feng Qiud, Chun-Jie Zhaoa,*,
Fu-Li Zhangb, and Zhe-Zhou Yangb
a School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016 China
b Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, 201203 China
c School of Pharmacy, Fudan University, Shanghai, 201203 China
d College of Chemistry and Material Science, Shandong Agricultural University, Taian, 271018 China
*e-mail: 75372127@qq.com
Received February 21, 2020; revised February 28, 2020; accepted May 17, 2020
Abstract—A one-pot synthesis of papaverine hydrochloride with 99.6% purity was performed using xylene as
solvent for the entire process. The critical parameters of each step, as well as the impurities generated, were
identified. The overall yield was improved to 63%. The proposed synthetic procedure is suitable for industrial
production.
Keywords: papaverine hydrochloride, one-pot synthesis, impurities, efficiency
DOI: 10.1134/S1070428020070258
INTRODUCTION
possible, which results in increased production costs
and reduced atom economy. Finally, the use of Pd/C as
a dehydrogenation catalyst requires a high temperature.
Therefore, development of an economical, efficient,
practical, and robust synthetic route for industrial
production is highly desired, and such process is
described in the present article.
In 1978, papaverine hydrochloride (1), promoted
under the trade name Oxadilene, was marketed in
France for the treatment of ischemia, as well as kidney,
gallbladder, and gastrointestinal visceral fistulae
caused by brain, heart, and peripheral vasospasms [1].
There are many ways to synthesize papaverine
hydrochloride [2], and the general route [3–5] used for
its synthesis is shown in Scheme 1. First, 3,4-dime-
thoxyphenylacetic acid (2) was reacted with SOCl2 in
toluene to form 3,4-dimethoxyphenylacetyl chloride.
The reaction of 3,4-dimethoxyphenylacetyl chloride
with 2-(3,4-dimethoxyphenyl)ethanamine (3) in di-
chloromethane at room temperature for 3 h gave amide
4. The latter was treated with POCl3 in acetonitrile at
80°C to generate dihydroisoquinoline derivative 5, and
the latter was dehydrogenated in toluene over Pd/C at
230°C to yield papaverine (6). Finally, papaverine (6)
was converted to papaverine hydrochloride (1) by
treatment with a solution of hydrogen chloride in
ethanol.
RESULTS AND DISCUSSION
The proposed synthetic process involves the follow-
ing four steps. First, 3,4-dimethoxyphenylacetic acid
(2) and 2-(3,4-dimethoxyphenyl)ethanamine (3) re-
acted at high temperature [6]. Amide 4 reacted with
POCl3 to yield imine 5 [7]. Imine 5 was dehydro-
genated with Raney nickel at high temperature [8] to
form papaverine 6, which was treated with hydro-
chloric acid to yield papaverine hydrochloride (1)
(Scheme 1; i–iv).
2-(3,4-Dimethoxyphenyl)-N-[2-(3,4-dimethoxy-
phenyl)ethyl]acetamide (4) was prepared by the con-
densation of 3,4-dimethoxyphenylacetic acid (2) and
2-(3,4-dimethoxyphenyl)ethanamine (3) in xylene with
azeotropic removal of water at different temperatures
(acid 2 is insoluble in xylene at temperatures below
130°C) [6]. The obtained results are shown in Table 1.
The process shown in Scheme 1 would first gen-
erate acid waste, which is contrary to the requirements
of green environmental protection. In addition,
frequent solvent changes makes solvent recycling im-
1295

WEN-SHUAI YU et al.
1296
Scheme 1.
General route
MeO
MeO
MeO
COOH
SOCl2, PhMe
COCl
MeO
2
MeO
MeO
NH2
MeO
(3)
H
N
N
MeO
MeO
OMe
MeO
NaHCO3, H2O/CH2Cl2
POCl3, MeCN
OMe
OMe
O
OMe
4
5
MeO
MeO
MeO
MeO
N
N · HCl
Pd/C, PhMe
HCl/EtOH
OMe
OMe
OMe
OMe
6, Papaverine
1, Papaverine hydrochloride
One-pot process
i
ii
iii
iv
2
+
3
4
5
6
1
Reagents and conditions: i: xylene, 150°C, 17 h; purity 95.03%; ii: POCl3, xylene, 80°C, 1.5 h; purity 98%; iii: Raney nickel, xylene,
130°C, 20 h; purity 92.56%; iv: hydrochloric acid, ethanol, H2O, followed by recrystallization; purity 99.6%; overall yield 63%.
By-products
MeO
N
MeO
4
5
+
OMe
OMe
O
7
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
N
N
NH
N
OMe
OMe
OMe
OMe
OMe
OMe
O
HO
11
12
8
9
10
The reaction required 17 h, and the conversion was
95% at 150°C (entry no. 2); the remaining 3.91% of 2
and 1.07% of 3 did not change over time.
(3,4-dimethoxyphenyl)methanone (7) as oxidation by-
product. According to the HPLC data, the amount of
ketone 7 can be reduced to 0.8% by controlling the
amount of phosphoryl chloride (Table 2, entry no. 3).
The optimal amount of phosphoryl chloride was found
to be 0.75 equiv.
In the next step, phosphoryl chloride was added to
the reaction mixture obtained in the previous step, and
the mixture was heated at 80°C [7]. Apart from
targeted 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dime-
thoxy-3,4-dihydroisoquinoline (5), the mixture con-
tained (6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)-
Dihydroisoquinoline 5 and a dehydrogenation
catalyst were reacted at high temperature to form
papaverine 6 [8]. We tested several dehydrogenation
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 7 2020

ONE-POT SYNTHESIS OF PAPAVERINE HYDROCHLORIDE
1297
Table 1. Condensation of 3,4-dimethoxyphenylacetic acid (2) and 2-(3,4-dimethoxyphenyl)ethanamine (3) in xylene at
different temperatures
Yield, % (HPLC)
Entry no.
Temperature, °C
Reaction time, h
2
3
4
1
2
3
130
150
170
27
17
17
3.72
3.91
3.93
1.32
1.07
1.12
94.96
95.03
94.95
Table 2. Determination of the stoichiometry of the cyclization reaction 4 → 5 (+7)
Yield, % (HPLC)
Amount of POCl3,
Entry no.
Reaction time, h
equiv
4
5
7
1
0.5
0.6
0.75
1
6
10
78
3.2
2.5
0.8
1.2
10
2
3.5
1.5
1
2.73
NDa
ND
ND
91.81
98
3
4
5
97.2
95
2
1
a Not detected.
Table 3. Effect of different catalysts on the dehydrogenation of 5 to form 6
Yield, % (HPLC)
Entry no.
Catalyst
Pd/C
5
6
8
9
10
12
11
3.5
11
12
1a
2a
3a
4b
5a
ND
13.3
ND
ND
5.8
67.4
21
0.9
0.7
1.2
5.8
0.5
0.9
0.7
1.2
5.8
0.5
15.3
22.7
3.64
4.2
Cobalt
30.6
0.7
Nickel
92.56
76.2
27.8
0.7
3.2
5.2
Nickel
4.8
Cobalt oxide
35.6
24.6
a Temperature 130°C, light-proof reaction.
b Temperature 130°C, exposure to light.
Table 4. Temperature effect on the dehydrogenation of 5 to form 6a
Entry no.
Temperature, °C
Reaction time, h
Yield of 6,b % (HPLC)
1
2
3
4
100
110
130
150
25
23
20
20
68.75
73.35
92.56
78.82
a Raney nickel-to-5 weight ratio (0.4–0.6):1.
b Only the HPLC peaks for 5 and 6 were integrated.
catalysts, such as Pd/C [9], Raney cobalt, Raney
nickel, and cobalt oxide and found that Raney nickel
was ideal as the dehydrogenation catalyst (Table 3,
entry no. 3). Therefore, we continued to optimize the
reaction conditions by using Raney nickel. In the
absence of light, the major impurities were compounds
8 (5.8%), 9 (5.8%), 10 (4.8%), 11 (3.2%), and 12
(9.3%) (Table 3, entry no. 4). Compounds 8 and 9 are
likely to result from photodegradation of 10 [10]. To
verify this assumption, ketone 10 was added to xylene
and Raney nickel, and the mixture was irradiated with
strong light with stirring at a high temperature [10]. In
fact, compound 10 was found to decompose to 8 and 9.
The amounts of the latter could be reduced from 5.8 to
1.2% by protection from light (Table 3, entry nos. 3, 4).
Ketone 10 was formed via dehydrogenation of 7.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 7 2020

WEN-SHUAI YU et al.
Table 5. Effect of the amount of Raney nickel on the dehydrogenation of 5 to form 6a
1298
Yield,c % (HPLC)
Entry no.
Weight ratio Raney Ni/5b
Reaction time, h
5
30
0
6
1
2
3
(0.1–0.3):1
(0.4–0.6):1
(0.7–1.0):1
25
20
20
51
92.56
87.52
0
a Reaction temperature 130°C.
b The weight of nickel was the wet weight.
c Only the HPLC peaks for 5 and 6 were integrated.
Impurities 11 and 12 were produced by the reduction
of 10 and 5, respectively, by the generated hydrogen.
When the reaction time was prolonged, compound 12
was partially converted to papaverine 6 and eventually
reduced to 3.64% (Table 3, entry no. 3). Therefore, we
used nitrogen to remove hydrogen and minimize this
side reaction. The effect of the dehydrogenation tem-
perature is shown in Table 4. The optimal temperature
was 130°C (Table 4, entry no. 3). The amounts of
Raney nickel used for the reaction are shown in
Table 5. The conversion was the highest when the
catalyst-to-5 ratio was (0.4–0.6):1 (entry no. 3).
(xylene), and the one-pot method reduces loss of inter-
mediates. Compared to the general route, the total yield
was significantly increased (to 63%).
EXPERIMENTAL
All solvents and reagents were purchased from
suppliers and were used without further purification.
NMR spectra were recorded on a Bruker Avance III
400/600 MHz spectrometer in CDCl3. Mass spectra
were recorded on an Agilent 6210 series single
quadrupole LC/MS. The reactions were monitored by
HPLC, and the purity was calculated according to the
HPLC peak areas. The HPLC analyses were performed
using the standard method on a Dionex UltiMate 3000
HPLC instrument using a Syncronis C18 column
(250 mm×4.6 mm, 5 μm) at 40°C, flow rate
1 mL/min; UV detector (λ 245 nm); duration 45 min;
mobile phases: A: 0.2% sodium heptanesulfonate and
0.2% potassium dihydrogen phosphate in water,
H2O/MeOH 7:3, pH 3.2; gradient elution program,
time (min)/% B: 0/5, 30/50, 20/15, 35/60, 40/60,
40/5, 45/5.
Finally, papaverine 6 and concentrated hydrochloric
acid (36%) were reacted in ethanol to obtain papa-
verine hydrochloride (1); ethanol and water were main-
tained at a ratio of 7.7:1 ratio to obtain a good yield
(63%) of highly pure (99.6%, single impurity less than
0.1%) papaverine hydrochloride of ICH-grade quality.
For the entire process, we used only two solvents,
xylene and ethanol. The number of solvents was
reduced from the previous four (toluene, dichloro-
methane, acetonitrile, and ethanol) to two, and the
solvent amount was reduced from the previous 13.5 L
to 5.04 L (Table 6).
2-(3,4-Dimethoxyphenyl)-N-[2-(3,4-dimethoxy-
phenyl)ethyl]acetamide (4). A mixture of 3,4-dime-
thoxyphenylacetic acid (2, 300 g, 1.66 mol) and
2-(3,4-dimethoxyphenyl)ethanamine (3, 325 g,
1.66 mol) in xylene (3 L) was stirred at 150°C for 17 h
with azeotropic removal of water [5]. The reaction was
monitored by HPLC until initial compounds 2 and 3
comprised less than 5% in total or until 95% conver-
sion to amide 4 was attained.
In conclusion, we have developed a recoverable and
cost-effective one-pot route to generate papaverine
hydrochloride that is suitable for industrial production.
The proposed synthetic route utilizes only commercial
and inexpensive reagents and only one solvent
Table 6. Amounts of solvents (L) used in the general and
new synthetic routes
General route
Dichloromethane
Toluene
New one-pot route
1-[(3,4-Dimethoxyphenyl)methyl]-6,7-dime-
thoxy-3,4-dihydroisoquinoline (5). Phosphoryl
chloride (175.8 g, 1.15 mol) was added to the reaction
solution obtained in the previous step, and the solution
was heated at 80°C for 2 h; the HPLC peaks were
integrated to confirm that the conversion was complete.
3
Ethanol
Xylene
2.04
4.5
3
3
Acetonitrile
Ethanol
3
Total
13.5
Total
5.04
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 7 2020

ONE-POT SYNTHESIS OF PAPAVERINE HYDROCHLORIDE
1299
An aqueous solution of sodium hydroxide (276 g,
FUNDING
6.9 mol, 0.02 M) was then added, and the mixture was
stirred for 30 min and allowed to settle down, the
organic phase was separated, and the aqueous phase
was extracted once with xylene and combined with the
organic phase. The purity of 5 was 98%.
We thank the Engineering Research Center for the Im-
provement & Industrialization of Pharmaceutical Processes
for financial support.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
SUPPLEMENTARY MATERIALS
1-[(3,4-Dimethoxyphenyl)methyl]-6,7-dime-
thoxyisoquinoline (6). The organic phase obtained in
the previous step was transferred to a 5-L reaction
flask, Raney nickel (260 g, 3.04 mol) was added, and
the mixture was heated at 130°C for 8 h; compound 5
was completely converted (according to HPLC). The
amount of by-product 12 was approximately 30%;
when the mixture was further heated at that tempera-
ture for 20 h, the amount of 12 decreased to 3.64%.
The purity of 6 was 92.56%. Finally, the catalyst was
filtered off.
Supplementary materials are available for this article at
https://doi.org/10.1134/S1070428020070258 and are acces-
sible for authorized users.
REFERENCES
1. Leslie, A., Mulinos, M.G., and Scott, W.S., Jr., Proc.
Soc. Exp. Biol. Med., 1940, vol. 44, p. 625.
1-[(3,4-Dimethoxyphenyl)methyl]-6,7-dime-
thoxyisoquinoline hydrochloride (1). The organic
phase obtained in the previous step was evaporated to
dryness. Absolute ethanol (2.04 L) was added,
36% hydrochloric acid (121.94 g, 1.2 mol) was then
added at room temperature, and the mixture was stirred
for 1 h. The solid product was filtered off; it had
a purity of 99%. Crude 1 and pure water (0.265 L)
were placed in a 3-L reactor and heated under reflux
for 20 min. Absolute ethanol (2.04 L) was slowly
added over a period of 30 min to the clear solution.
Crystal seeds (0.1 g) were added to the solution, and
the solution was stirred at 70°C for 1 h. The mixture
was allowed to cool to room temperature over 2 h. The
product was formed as a white needle-like crystalline
solid (361 g, yield 63%, HPLC purity 99.6%; single
impurity less than 0.1%). mp 223.7–224.4°C [11].
1H NMR spectrum (600 MHz, CDCl3), δ, ppm: 8.26 d
(1H, J = 6.5 Hz), 7.88 d (1H, J = 6.5 Hz), 7.63 s (1H),
7.24 d (1H, J = 2.0 Hz), 6.93 d.d (1H, J = 8.2, 2.0 Hz),
6.75 d (1H, J = 8.3 Hz), 4.99 s (2H), 4.11 s (3H), 4.04 s
(3H), 3.85 s (3H), 3.80 s (3H). 13C NMR spectrum
(151 MHz, CDCl3), δC, ppm: 157.00, 154.09, 152.59,
149.52, 148.38, 136.92, 129.33, 128.04, 122.52,
121.54, 120.81, 112.54, 111.33, 106.02, 104.96, 56.88,
56.55, 56.31, 55.87, 36.52. Mass spectrum: m/z 339.1
[M + H]+. C20H21NO4. Calculated: M + H 339.15.
https://doi.org/10.3181/00379727-44-11550
2. Galat, A., J. Am. Chem. Soc., 1951, vol. 73, p. 3654.
https://doi.org/10.1021/ja01152a027
3. Kadam, H.K. and Tilve, S., Arkivoc, 2018, vol. 2018,
part (iii), p. 184.
https://doi.org/10.24820/ark.5550190.p010.433
4. Yu, R., Zhou, Y., Huan, Y., Liu, Q., Shen, Z., Liu, Z.,
Yaoxue Xuebao, 2011, vol. 46, p. 311.
5. Ivanova, B. and Spiteller, M., Nat. Prod. Commun.,
2012, vol. 7, p. 581.
https://doi.org/10.1177/1934578x1200700508
6. Yamamoto, Y., Tabuchi, Y., Baba, A., Hideshima, K.,
Nakano, M., Miyawaki, A., and Tomioka, K.,
Heterocycles, 2014, vol. 88, p. 1311.
https://doi.org/10.3987/COM-13-S(S)101
7. Kakhki, S., Shahosseini, S., and Zarghi, A., Iran. J.
Pharm. Res., 2014, vol. 13 (suppl.), p. 71.
8. Zhang, K., Zhang, J., Guo, W., Zhu, H., and Guo, Z.,
CN Patent no. 105541714A, 2016.
9. Minachev, Kh.M., Kharlamov, V.V., and Ryashentse-
va, M.A., Bull. Acad. Sci. USSR, Div. Chem. Sci., 1988,
vol. 37, p. 2405.
https://doi.org/10.1007/BF00952605
10. Stermitz, F.R., Pua, R., and Vyas, H., J. Chem. Soc.,
Chem. Commun., 1967, no. 7, p. 326.
https://doi.org/10.1039/c1967000326a
11. Solodukhina, L.A. and Abrosimova, L.A., RU Patent
no. 2647583C2, 2018.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 7 2020