Novel and practical synthesis of vonoprazan fumarate

Article abstract of DOI:10.1080/00397911.2017.1318924

A novel and practical strategy for the synthesis of vonoprazan fumarate 1, a novel potassium-competitive acid blocker, has been developed. Vonoprazan fumarate was obtained through a four-step process starting from 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate and including ester hydrolyzing, methylamine substitution, sulfonyl chloride substitution, and amide reduction. Key to the strategy is the amide reduction taking a novel and practical protocol. The main advantages of this route include two parts: controllable impurity and acceptable overall yield.

Full text of DOI:10.1080/00397911.2017.1318924

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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A Novel and Practical Synthesis of Vonoprazan
Fumarate
Qian-Ying Yu, Huang Zeng, Kai Yao, Jian-Qi Li & Yu Liu
To cite this article: Qian-Ying Yu, Huang Zeng, Kai Yao, Jian-Qi Li & Yu Liu (2017): A
Novel and Practical Synthesis of Vonoprazan Fumarate, Synthetic Communications, DOI:
10.1080/00397911.2017.1318924
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Date: 22 April 2017, At: 00:24

A Novel and Practical Synthesis of Vonoprazan Fumarate
Qian-Ying Yu1,2, Huang Zeng1,2, Kai Yao1,2, Jian-Qi Li1,2, Yu Liu1,2
1Novel Technology Center of Pharmaceutical Chemistry Shanghai Institute of
Pharmaceutical Industry, Shanghai, China 2Shanghai Engineering Research Center of
Pharmaceutical Process, Shanghai, China
Corresponding author: Dr. Yu Liu, Associate Researcher , E-mail:
liuyu_tianjin@126.com
Abstract
A novel and practical strategy for the synthesis of vonoprazan fumarate 1, a novel
potassium-competitive acid blocker, has been developed. Vonoprazan fumarate was
obtained via a four-step process starting from 5-(2-fluorophenyl)-1H-pyrrole-3-
carboxylate and including ester hydrolyzing, methylamine substitution, sulfonyl chloride
substitution and amide reduction. Key to the strategy is the amide reduction taking a
novel and practical protocol. The main advantages of this route include two parts:
controllable impurity and acceptable overall yield.
Graphical Abstract
KEYWORDS: Vonoprazan fumarate; synthesis; novel and practical; amide reduction
INTRODUCTION
1

Vonoprazan fumarate (TAK-438, 1, Fig. 1) is a novel potassium-competitive acid blocker
which was approved in Japan in February 2015 for the treatment and prevention of acid-
related diseases. It has high solubility and stability over a broad pH range [1], with more
potent and longer-lasting acid suppression effect than the conventional proton pump
inhibitors (PPIs)[2].Vonoprazan provides a new option for patients with acid-related
diseases that are refractory to, or inadequately controlled by, the treatment with PPIs[7].
Vonoprazan fumarate has great clinical potential for its therapeutic effects against peptic
ulcers and gastro-esophageal reflux diseases, as well as the eradication of Helicobacter
pyloric. So, it would be a great interest to develop a novel and practical synthesis route
for the process development researchers.
As outlined in Scheme 1, the original approach [4,5]to synthesizing vonoprazan fumarate
was reported by Takeda beginning with the preparation of 5-(2-fluorophenyl)-1H-
pyrrole-3-carbaldehyde 3. Aldehyde 3 was then reacted with pyridine-3-sulfonyl chloride
4, followed by a reductive amination with methylamine to provide the free base, which
was subsequently treated with fumaric acid to give 1[6]. Two ways were reported for the
preparation of intermediate 3, one starts from commercially available ethyl 5-(2-
fluorophenyl)-1H-pyrrole-3-carboxylate 2, through a reduction reaction and catalytic
oxidation to afford aldehyde 3[7] (Route A, Scheme 1), the other uses 5-(2-fluorophenyl)-
1H-pyrrole-3-carbonitrile 6 as the starting material, which was converted to aldehyde 3
via a catalytic hydrogenation in acetic acid (Route B, Scheme 2). In our laboratory
synthesis of 1 through intermediate 3, we found that the original synthesis process has
two problem to be resolved: the first problem was that 3 was chemically unstable and
2

would be partly degraded to 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylic acid (8, Fig. 2)
under storage condition; and the other problem was the formation of by-product di-(5-(2-
fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (7, Fig. 2)
in the last step, which was difficult to remove from the product and the formation of this
impurity couldn’t be avoided after careful condition screening.
In order to avoid the degradation of 3 and the formation of two-substituted byproduct 7,
we designed a new synthetic route for vonoprazan fumarate through an intermediate 5-(2-
fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxamide 12 via
amide reduction (Scheme 2). Retrosynthetically the planned synthesis can be viewed as
delivering amide 12 via combining carboxylic acid 8, sulfonyl chloride 4 and
methylamine. Compound 8 was a substrate that was expected to derive from the
hydrolysis of reported compound 2.
RESULTS AND DISCUSSION
At the beginning, we tried to achieve the final product through route C (Scheme 3). The
starting material 2 and sulfonyl chloride 4 would be coupled to give ethyl ester 9 via a
nucleophilic substitution reaction. Then ethyl ester derivatives 9 could be hydrolyzed to
provide 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylic acid 10.
The reaction between 10 and methylamine in the presence of trimethylamine and EDCI
would furnish amide 12, which could be subsequently reduced to afford vonoprazan
fumarate 1.
3

We prepared compound 9 in an acceptable yield of 74.9% using LDA as the base, but
there was a problem in the synthesis of 12 through route C (Scheme 3). We tried to
prepare 12 through ester hydrolyzation and amine coupling, or ester and amine exchange,
but all the efforts were proved to be ineffective because the sulfonamide group in
compound 10 was hydrolyzed easily. So, we transferred our efforts to synthesize 12
through route D (Scheme 3).
Because of the instability of the sulfonamide, we decided to introduce this moiety at a
later stage of the route. In route D, methylamine and compound 8, the hydrolysate of
starting material 2, were coupled first to furnish 5-(2-fluorophenyl)-N-methyl-1H-
pyrrole-3-carboxamide 11 in the presence of trimethylamine and EDCI. Then compound
11 was converted to amide 12 by the treatment with 4. Finally, vonoprazan fumarate 1
was obtained through the reduction of 12 and the salt formation step.
Intermediate 8 was obtained in 93.0% yield via hydrolyzing 2 in 4% sodium hydroxide
methanol/ H2O (v: v=1.4:1) solution at 600C for 3h. Then, 8 was coupled with
methylamine to give 11 in the yield of 91.2% under the condition of EDCI and
triethylamine. In the preparation of the key intermediate 12, we tried to repeat the same
conditions as for the preparation of compound 9, but the yield was only 18.3% (Table 1,
Entry 4). There was no product observed under NaH, t-BuOK, or TEA (Table 1, Entry 1,
2, 3). n-BuLi yields compound 15 in 70.2% yield at -780C, while the yield decreased with
the increase of reaction temperature, and there was no product observed when the
temperature was raised to -300C (Table 1, Entry 5, 6, 7, 8).
4

Amide derivative 12 reduction was the crucial reaction step in synthesizing compound 1.
There was no product observed under the reaction of BH3, Red-Al and NaBH4-BF3, while
the amide could be reduced with LiAlH4 in a satisfactory conversion (Table 2). The crude
product 1 was obtained by reflux in ethyl acetate with fumarate. Finally, Vonoprazan
fumarate could be purified by recrystallization in methanol aqueous solution (HPLC:
99.9%).
CONCLUSION
In conclusion, we have developed a novel and practical method for the synthesis of
vonoprazan fumarate starting from ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate 2.
The synthesis was accomplish in four linear steps with a total yield of 41.3%. In
comparison to the other reported method, our route has advantages such as less by-
products, simplified work-up operation and more stable intermediate, therefore is more
suitable for scale up.
EXPERIMENTAL
General: Reagents and solvents were obtained from commercial suppliers. All reactions
were monitored by thin layer chromatography using commercial silica gel plates. The
purity of products was detected by HPLC on Ultimate 3000, Melting points were
measured by YRT-3 melting-point tester. 1H NMR and 13C NMR spectra were recorded
on Bruker AVANCE III 400 MHz and 600MHz. HR-MS was recorded on MicrOTOF-Q
II.
5

5-(2-Fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxamide
(12). Compound 11 (10.00g, 45.9mmol) was suspended in tetrahydrofuran (100mL) and
was slowly added n-butyl lithium at -78 0C under the nitrogen atmosphere; After stirring
for 0.5 h, 3-pyridinesulfonyl chloride 4 was added at the same temperature, and the
reaction mixture was stirred for 3h. Water (25mL) was added, and the mixture was
extracted with ethyl acetate. The extract was washed with sodium hydrogen carbonate
solution and brine, dried over anhydrous sodium sulfate, and concentrate under reduced
pressure. The residue was purified by silica gel column chromatography
(dichloromethane-methanol, 30:1) to give compound 12 (11.1g, yield 67.3%, purity
98.9%). m.p.200.2~202.0 0C; 1H NMR (400 MHz, CDCl3) δ 8.85~8.75 (m, 1H), 8.57 (d,
J = 2.1Hz, 1H), 7.97~7.98 (d, J = 1.8Hz, 1H), 7.70~7.73 (m, 1H), 7.42~7.48 (m, 1H),
7.34~7.37 (m, 1H),7.15~7.17 (m, 2H), 7.01~7.06 (t, J = 8.9Hz, 1H), 6.49 (d, J = 1.8 Hz,
1H), 5.97 (d, J = 3.7 Hz, 1H), 2.97 (d, J = 4.9 Hz, 3H); 13C NMR (150 MHz, DMSO-d6)
δ 162.47, 159.90&161.54(d, JCF = 246Hz),155.76, 147.54, 135.47, 134.37, 133.41,
132.42&132.47 (d, JCF = 7.5 Hz), 128.42, 125.25, 125.19, 124.41(d, JCF = 3Hz), 124.28,
118.39&118.50(d, JCF = 16.5Hz), 116.28, 115.68&115.82 (d, JCF = 21 Hz), 26.15;
HRMS (ESI) calcd for C17H14FN3O3S [M+H]+ 360.0813, found 360.0813.
Vonoprazan Fumarate (1). To a solution of compound 12 (5.0g, 13.9mmol) in
tetrahydrofuran (40mL) was slowly added a solution of LiAlH4 under the nitrogen
atmosphere at 0 0C, and the mixture was stirred for 5h. After the completion of the
reaction, tetrahydrofuran in water was added and extracted with ethyl acetate. The extract
6

was washed with sodium hydrogen carbonate solution and brine, dried over anhydrous
sodium sulfate. Fumaric acid (1.6g, 13.9mmol) was added in the mixture during the
stirring at 25 0C for 30 min. After filtration, the filter cake is recrystallization with 50ml
of 70% methanol solution. The final product vonoprazan fumarate (1) is obtained after
filtration (4.6g, yield 72.4%, purity 99.9%). m.p. 206.2~207.6 0C; 1H NMR (600 MHz,
DMSO-d6) δ 8.82~8.83 (d, J = 4Hz, 1H), 8.57 (s, 1H), 7.89~7.90 (d, J = 4Hz, 1H), 7.82
(s, 1H), 7.52~7.57 (m, 2H), 7.21~7.22 (t, J = 4, 1H), 7.10~7.16 (m, 2H), 6.70 (s, 2H),
6.46(s, 1H), 4.12(s, 2H), 2.72 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 168.18,
158.90&161.35(d, JCF = 245Hz), 155.01, 146.79, 135.11, 134.67, 134.21, 132.61, 131.74,
131.66, 128.31, 124.53, 124.31, 123.87(d, JCF = 3Hz), 120.63, 118.26&118.41(d, JCF =
15Hz), 115.14&115.36(d, JCF = 22Hz), 43.58, 31.84; HRMS (ESI) calcd for
C17H16FN3O2S [M+H]+ 346.1020, found 346.1019.
SUPPLEMENTAL MATERIAL
Full experimental detail, 1H and 13C NMR spectra, HRMS, HPLC. This material can be
found via the ‘Supplementary Content’ section of this article’s webpage.
ACKNOWLEDGMENT
This project was spouted sponsored by the Shanghai Institute of Pharmaceutical Industry.
REFERENCES
7

1
Luo, H.J.; Deng, W.Q.; Zou, K.; Protonated form: the potent form of potassium
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Triple Therapy with Vonoprazan, Amoxicillin, and Clarithromycin or Metronidazole: A
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3
Matsukawa, J.; Hori, Y.; Nishida, H.; et al. A comparative study on themodes of
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Kajino, M.; Hasuoka, A.; Nishida, H.; 1-heterocyclylsulfonyl, 2-aminomethyl, 5-
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8

Table 1 Reaction condition screening of the sulfonyl chloride substitution with 11
Entry Base
Time(h) Temp(0C) Yield of compound 12(%)
1
2
3
4
5
6
7
8
NaH
12
0
No reaction
No reaction
No reaction
18.3%
t-BuOK 12
0
TEA
12
8
50
-78
-78
-60
-45
-30
LDA
n-BuLi
n-BuLi
n-BuLi
n-BuLi
3
67.3%
3
43.5%
3
19.5%
3
No reaction
9

Table 2 Optimization of the reducing reagent
Entry Reducing reagent Yield of compound 1(%)
1
2
3
4
5
BH3
No reaction
No reaction
72.4%
Red-Al
LiAlH4
NaBH4-BF3
NaBH4-AlCl3
No reaction
Trace
10

Scheme 1.
11

Scheme 2.
12

Scheme 3.
13

Figure 1.
14

Figure 2.
15