Concise Synthesis of Key Intermediates of Pyriftalid and Paquinimod via Hydrogenation Method

Article abstract of DOI:10.1021/acs.oprd.7b00177

An efficient and scalable synthesis of 7-amino-3-methylisobenzofuran-1(3H)-one (1) and 2-amino-6-ethylbenzoic acid (2) has been developed via a one-step catalytic hydrogenation. The triethylammonium salt of 2-acetyl-6-nitrobenzoic acid was used as the sta

Full text of DOI:10.1021/acs.oprd.7b00177

Article
pubs.acs.org/OPRD
Concise Synthesis of Key Intermediates of Pyriftalid and Paquinimod
via Hydrogenation Method
Zhong Li,† Bing Li,‡ An-Jiang Yang,† and Fu-Li Zhang*,†
†Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmacetical Industry, 285 Gebaini Road, Pudong, Shanghai
201203, China
‡Zhejiang University of Technology, 18 Chaowang Road, Xiacheng, Hangzhou 310014, China
S
* Supporting Information
ABSTRACT: An efficient and scalable synthesis of 7-amino-3-methylisobenzofuran-1(3H)-one (1) and 2-amino-6-ethylbenzoic
acid (2) has been developed via a one-step catalytic hydrogenation. The triethylammonium salt of 2-acetyl-6-nitrobenzoic acid
was used as the starting material and 1 was prepared in a biphasic solvent system of toluene/H2O, while 2 was obtained when the
solvent was replaced with H2O. Intermediates 1 and 2 could be used to synthesize Pyriftalid and Paquinimod, respectively.
prepare paquinimod.6,7 Compound 3 is also used as the starting
material to prepare 2, via two-step reduction by catalytic
INTRODUCTION
Pyriftalid, an acetolactate synthase (ALS) inhibitor to block the
biosynthesis of branched-chain amino acids, can be used to
■
hydrogenation, with PtO2 as catalyst first, and then Raney-Ni, in
90.0% overall yield (Scheme 2).8 Obviously, the catalyst PtO2
control Echinochloa, Leptochlao, Brachiaria, Setaria, and
Ischemeum spp for the improvement of rice production.1−3 7-
increases the cost dramatically; also, the continuous usage of two
catalysts results in inefficient production and inconvenient
catalyst recovery.
Amino-3-methylisobenzofuran-1(3H)-one 1 is used as a key
intermediate in the synthesis of Pyriftalid. Compound 1 can be
prepared from 2-acetyl-6-nitrobenzoic acid 3 (Scheme 1), via a
Scheme 2. Reported Synthetic Route of Key Intermediate 2
Scheme 1. Reported Synthetic Route of Key Intermediate 1
In order to explore an economical and industrial process for
the production of 1 (for Pyriftalid) and 2 (for Paquinimod), we
intended to develop a novel one-step catalytic hydrogenation
method, using 3 as the starting material.
RESULTS AND DISCUSSION
■
As previously reported,4 reduction of 3 in a single step afforded 1
in low yield and purity. On this basis, we investigated several
types of catalysts and solvents, aiming to improve the yield and
purity (Table 1). The reduction process follows the order 3−4−
1−6−2.8,9 The nitro of 3 was reduced to give amino compound
4, and the benzyl hydroxyl of 4 was then reduced to give lactone
compound 1. Partial hydrolysis of 1 produced 6, and the benzyl
hydroxyl of 6 was subsequently reduced to obtain 2. Raney-Ni
was unable to reduce 4 completely unless HCOOH was added,
but 14.69% 2 was generated under these conditions (entries 1,
2). As Pd/C was screened, HCOOH did not work and Pd-
ethylene diamine complex also turned out to be ineffective
(entries 3, 4). Toluene appeared to be a better solvent (entry 6);
when H2O was added, only 2.60% 4 remained and the purity of 1
two-step reduction with hydrogen and NaBH4 respectively in
75.4% overall yield (Path A) or 93.7% yield when the order of
reducing agents is reversed (Path B). However, usage of NaBH4
leads to a relatively high cost, and the two-step methods result in
inefficient production. Alternatively, 1 can also be obtained
directly by catalytic hydrogenation from 3 in 89.7% yield (Path
C), with an unacceptable purity of 86.4%, which restricts its
application in industry.4
Paquinimod belongs to the class of 3-quinolinecarboxamide
derivatives, whose molecular target has been identified as
S100A9 protein. A phase II study of Paquinimod for patients
with systemic lupus erythematosus (SLE) has been completed.5
2-Amino-6-ethylbenzoic acid 2 is the key intermediate used to
Received: May 16, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.7b00177
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Table 1. Conditions for the Hydrogenation of 3
c
HPLC (%)
a
b
entry
catalyst
R-Ni
solvent
ethanol
pressure (atm)
T/t (°C/h)
4
1
2
1
2
3
4
5
6
7
8
9
10
10
5
80/20
30.89
ND
46.96
72.32
7.20
15.30
14.69
0.13
1.42
0.78
1.95
1.21
ND
d
d
R-Ni
ethanol/HCOOH
ethanol/HCOOH
ethanol
80/20
Pd/C
Pd/C (en)
Pd/C
Pd/C
Pd/C
R-Co
110/24
110/60
110/24
110/18
110/18
110/18
110/18
74.90
37.02
54.82
9.33
e
10
5
39.53
37.58
72.30
86.73
0.39
dioxane
toluene
10
10
10
10
f
toluene/H2O
2.60
toluene
toluene
72.53
89.67
Pt/C
4.44
ND
a
Reaction conditions: 3 (2.00 g), catalyst (0.40 g), solvent (50 mL), autoclave, Model 4760 Pressure Reaction Apparatus, Parr Instrument Company,
b
c
d
e
Moline, IL USA, 300 mL. Bath temperature. Compositions were calculated from HPLC area. 2.5 mL of HCOOH was added. Pd-ethylene
diamine complex;10 10 mL of H2O was added.
f
Scheme 3. Proposed Reduction Process of Triethylammonium Salt of 3 in Toluene/H2O
Table 2. Conditions for Reduction of Triethylammonium Salt of 3 To Prepare 1
c
HPLC (%)
a
b
d
entry
catalyst
pressure (atm)
T/t (°C/h)
4
1
6
2
yield (%)
1
2
3
4
5
6
7
Pd/C
R-Ni
R-Ni
R-Ni
R-Ni
R-Ni
R-Ni
R-Ni
R-Ni
R-Ni
R-Ni
15
15
15
15
15
15
15
15
4
120/17
120/17
100/14
80/6
0.71
ND
ND
ND
ND
ND
4.08
64.65
0.52
0.09
ND
98.45
96.68
99.52
98.47
98.70
98.89
95.08
5.28
0.85
ND
ND
0.22
ND
0.09
ND
1.61
ND
ND
ND
ND
0.20
0.14
ND
ND
ND
ND
0.08
ND
ND
ND
63.9
76.0
87.5
91.3
95.7
95.1
27.9
ND
80/8
80/14
60/10
60/10
80/8
e
8
9
99.17
99.60
99.68
98.5
98.3
97.7
f
10
4
80/8
f
11
5
80/8
a
Reaction conditions: Triethylammonium salt of 3 (3.00 g), catalyst (0.50 g), toluene (30 mL), H2O (5 mL), the same autoclave as shown in Table
b
c
d
e
1. Bath temperature. Compositions of toluene phase were calculated from HPLC area. Isolated yield of 1. Compositions of aqueous phase of
entry 7. Reused Raney-Ni.
f
dramatically increased to 86.73% (entry 7). Both Raney-Co and
Pt/C were ineffective catalysts,13 as compound 4 was obtained as
the main product (entries 8, 9). The best result as shown in entry
7 was still not practical enough for scale-up production.
Based on the results of Table 1, it was clear that stopping the
reduction at lactone 1 would be challenging. Separating 1 from
the system as the reaction proceeds would be an attractive
solution. Fortunately, 1 is the only compound without an acidic
B
DOI: 10.1021/acs.oprd.7b00177
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Table 3. Conditions of Raney-Ni for Reduction of Triethylammonium Salt of 3 To Prepare 2
c
HPLC (%)
a
b
d
entry
base
pressure (atm)
T (°C)
4
1
6
2
yield (%)
1
not added
not added
15
14
20
20
18
18
20
20
14
11.5
9.5
80
0.17
0.33
0.68
59.50
ND
ND
ND
ND
ND
ND
ND
33.12
21.38
39.12
0.22
1.34
0.88
3.36
ND
64.05
75.09
7.42
ND
ND
ND
ND
ND
93.6
ND
ND
94.2
94.5
2
120
80
e
3
NaOH
f
4
ammonia
80
ND
5
Et3N (1.0 equiv)
Et3N (2.0 equiv)
Et3N (2.0 equiv)
Et3N (2.0 equiv)
Et3N (2.0 equiv)
Et3N (2.0 equiv)
Et3N (2.0 equiv)
120
120
110
100
120
120
120
9.53
0.63
0.48
0.59
1.52
0.86
0.72
1.79
89.34
98.30
92.89
74.59
97.14
98.22
93.45
6
1.04
7
6.61
8
22.92
1.57
9
10
11
0.56
4.77
ND
a
b
Reaction conditions: triethylammonium salt of 3 (6.20 g), Raney-Ni (1.00 g), H2O (45 mL), 8 h, the same autoclave as shown in Table 1. Bath
c
d
e
temperature. Compositions of reaction mixture were calculated from HPLC area. Isolated yield of 2. The starting material included 3, 1.1 equiv of
NaOH. The starting material included 3; adjust the reaction mixture to pH 11.0 with ammonia.
f
Table 4. Conditions of Pd/C for Reduction of Triethylammonium Salt of 3 To Prepare 2
c
HPLC (%)
a
b
d
entry
Pd/C (g)
pressure (atm)
T (°C)
4
1
6
2
yield (%)
1
2
3
4
5
1.00
1.00
1.00
1.00
0.50
15
15
11
5
80
10.58
0.96
41.10
5.64
1.03
1.38
1.39
0.41
0.80
47.25
92.02
98.22
36.07
68.54
ND
ND
92.7
ND
ND
90
100
100
100
0.30
ND
23.17
10.10
40.17
20.55
15
a
b
Reaction conditions: triethylammonium salt of 3 (6.20 g), H2O (45 mL), 8 h; the same autoclave as shown in Table 1. Bath temperature.
c
d
Compositions of reaction mixture were calculated from HPLC area. Isolated yield of 2.
group in the reduction process. Lactone 1 was further found to be
soluble in toluene but insoluble in weak alkaline water (pH = 10).
Based on this fact, 3 was prepared as its triethylammonium salt,
and toluene/H2O was selected as the biphasic solvent system. In
principle, the reduction would proceed in water; however, as
soon as lactone 1 is generated it presumably would partition
more favorably into the toluene layer and not be over-reduced
(Scheme 3).
Various conditions were investigated in the biphasic solvent
system (Table 2). When Pd/C was chosen as the catalyst, the
yield of 1 was 63.9% (entry 1). Raney-Ni turned out to be a
promising catalyst, as 1 was obtained in higher yield compared to
Pd/C in the same conditions (entry 2). The yield of 1 increased
significantly to 95.7% at a lower temperature of 80 °C (entry 5);
when the temperature was reduced to 60 °C, the yield dropped to
27.9%, and 4 became the main product which existed in aqueous
phase in the form of its triethylammonium salt (entries 7, 8). The
yield was 95.1% when the reaction time was prolonged to 14 h
(entry 6), which indicated 1 was stable at 80 °C. At a lower
pressure of 4 atm, 1 was obtained in higher purity and yield
(entry 9). Consequently, the reduction was performed as shown
in entry 9, and Raney-Ni could be recovered more than three
times (entries 10, 11). After the reduction was complete, the
toluene layer was separated, followed by evaporation of the
solvent, affording 1 in high yield and purity, while compounds 3,
4, 6, 2 stayed in water in the form of their triethylammonium
salts.
A further study focused on the synthesis of 2, which was a key
intermediate of Paquinimod. 2 can also be used for the
preparation of substituted pyrazolo[1,5-a]pyrimidine derivatives
as respiratory syncytial virus inhibitors and a nonpeptidic ligand
for the molecular imaging of inflammatory processes.11,12 The
triethylammonium salt of 3 could be used to prepare 2 if the
reduction was run in water (Table 3). As the reduction
progressed, the lactone compound 1 could not be separated
from the reaction system. Partial hydrolysis in alkaline solution
would produce 6. The benzyl hydroxyl of 6 would subsequently
be reduced to obtain 2. Various conditions were screened as
shown in Table 3, the catalyst was still Raney-Ni. The reduction
was initially carried out at 80 and 120 °C; less 1 remained as the
temperature increased, but the results were still unsatisfactory
(entries 1, 2). However, when the sodium or ammonium salt of 3
was used instead of its triethylammonium salt, only a trace of 2
was generated (entries 3, 4). Addition of an extra equivalent of
Et3N promoted the hydrolysis of 1 (entry 5). When 2.0 equiv of
Et3N was added, only 1.04% 1 remained and 2 was obtained in
C
DOI: 10.1021/acs.oprd.7b00177
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Organic Process Research & Development
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98.30% purity (entry 6). When the temperature was reduced to
110 and 100 °C, 1 could not be completely converted to 2
(entries 7, 8). The pressure could be reduced to 11.5 atm at a
temperature of 120 °C to give 98.22% purity of 2 with only 0.56%
of 1 remaining (entry 10). Further reduction of the pressure to
9.5 atm left 4.77% of 1 remaining after 8 h (entry 11). After the
reduction was complete, the aqueous phase was adjusted to pH
3.0−3.5 with hydrochloric acid, the product was extracted with n-
butyl acetate, and then the organic solvent was evaporated to
obtain 2. The reaction steps proceeded mostly by sequence;
reaction process data could be found in the Supporting
Information.
Conditions were investigated when the catalyst was Pd/C
(Table 4). The reduction was initially carried out at 80 °C;
41.10% 1 remained (entry 1). When the temperature was
increased to 90 °C, the result was still unsatisfactory (entry 2).
When the reduction was carried out at 100 °C/11 atm, 1 could be
completely converted to 2 (entry 3). At a lower pressure of 5 atm,
40.17% of 1 remained (entry 4). When the amount of Pd/C was
reduced to 50%, the reduction could not be completed in 8 h
(entry 5).
60 °C. The product was obtained as a white solid (465.2 g,
97.6%), with a purity of 99.20%. Mp 122.8−125.1 °C. Anal.
Calcd for C15H22N2O5: C, 58.05; H, 7.15; N, 9.03. Found: C,
57.82; H, 7.18; N, 8.89.
7-Amino-3-methylisobenzofuran-1(3H)-one (1). The trie-
thylammonium salt of 3 (341.1 g 1.10 moL) was added to water
(570 mL) and toluene (1680 mL), and then Raney-Ni (56.7 g)
was added to the mixture. After three vacuum/N2 cycles to
remove air, the stirred mixture was hydrogenated at 65 °C, 5 atm,
for 8 h. When the reaction was determined to be complete by
HPLC (compound 4 in aqueous phase ≤5%), the catalyst was
filtered off. The filtrate was separated to give the organic phase,
and the aqueous phase was extracted with toluene (1500 mL ×
2). Then the organic phases were combined and evaporated
under vacuum to give 1 as a white solid (170.4 g, 95.0%), with a
1
purity of 99.42%. Mp 77.3−78.5 °C (lit mp 80−81 °C4); H
NMR (400 MHz, DMSO) δ 7.34 (dd, J = 8.1, 7.3 Hz, 1H), 6.65
(d, J = 8.2 Hz, 1H), 6.61 (d, J = 7.3 Hz, 1H), 6.25 (s, 2H), 5.50 (q,
J = 6.6 Hz, 1H), 1.48 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz,
DMSO) δ 171.47, 152.83, 148.43, 136.06, 113.71, 108.29,
106.74, 77.46, 20.83.
CONCLUSIONS
2-Amino-6-ethylbenzoic Acid (2). The triethylammonium
salt of 3 (322.4 g, 1.04 moL) was added to water (2300 mL), and
then triethylamine (210.1 g, 2.08 moL) and Raney-Ni (52.0 g)
were added to the mixture. After three vacuum/N2 cycles to
remove air, the stirred mixture was hydrogenated at 110 °C, 15
atm, for 8 h. When the reaction was complete as determined by
HPLC (compound 1 ≤ 1.5%), the catalyst was filtered off. The
pH was adjusted to 3.0−3.5 with hydrochloric acid. The mixture
was extracted with n-butyl acetate (1800 mL× 3). Then the
organic phase was combined and evaporated under vacuum to
give 2 as a white loose solid (160.5 g, 93.5%), with a purity of
98.20%. Mp 107.3−108.2 °C (lit mp 107−109 °C8); 1H NMR
(400 MHz, DMSO) δ 8.04 (s, 2H), 7.10−6.97 (m, 1H), 6.58 (dd,
J = 8.2, 0.8 Hz, 1H), 6.42 (d, J = 7.0 Hz, 1H), 3.35 (s, 1H), 2.70
(q, J = 7.5 Hz, 2H), 1.11 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz,
DMSO) δ 170.70, 149.05, 144.82, 131.45, 117.43, 115.08,
114.29, 28.14, 16.59.
The triethylammonium salt of 3 (6.20 g, 0.02 moL) was added
to water (45 mL), and then Pd/C (1.00 g) was added to the
mixture. After three vacuum/N2 cycles to remove air, the stirred
mixture was hydrogenated at 100 °C, 11 atm, for 8 h. The catalyst
was filtered off. The pH was adjusted to 3.0−3.5 with
hydrochloric acid. Then the mixture was extracted with n-butyl
acetate (45 mL× 3). The organic phases were combined and
evaporated under vacuum to give 2 as a white loose solid (3.06 g,
92.7%), with a purity of 98.50%.
7-Amino-3-hydroxy-3-methylisobenzofuran-1(3H)-one (4).
Compound 3 (5.00 g, 23.9 mmoL) was added to ethanol (70
mL), and then Pd/C (3.70 g) was added to the mixture. After
three vacuum/N2 cycles to remove air, the stirred mixture was
hydrogenated at 40 °C, 8 atm, for 5 h. After the catalyst was
filtered off, the solvent was evaporated under vacuum to give 4 as
a yellow solid (4.26 g, 99.5%), with a purity of 97.14%. Mp
158.9−160.3 °C; 1H NMR (400 MHz, DMSO) δ 7.53 (s, 1H),
7.35 (dd, J = 8.1, 7.4 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 6.65 (d, J =
7.2 Hz, 1H), 6.26 (s, 2H), 1.65 (s, 3H); 13C NMR (100 MHz,
DMSO) δ 169.63, 151.96, 148.07, 136.17, 115.07, 108.66,
107.14, 106.14, 26.79.
■
An efficient and practical one-step catalytic hydrogenation
process for the synthesis of 1 and 2 has been developed. The
triethylammonium salt of 3 was used as the starting material.
Compound 1 was prepared in a biphasic solvent system of
toluene/H2O, while compound 2 was obtained when the solvent
was replaced with water. The reduction was further applied on
larger scale; both 1 and 2 were obtained in high, stable yield and
purity, which could be used as the key intermediate to synthesize
Pyriftalid and Paquinimod, respectively.
EXPERIMENTAL SECTION
General. H NMR and 13C NMR spectra were recorded
■
1
using a Bruker 400 MHz spectrometer. Chemical shift data are
reported in δ (ppm) from the internal standard TMS. Mass
spectra was recorded on an Agilent 6120B series single
quadrupole LC-MS. Melting points were measured on a WRS-
1B apparatus. Reaction was monitored by HPLC, and purity was
calculated from HPLC area. The HPLC analyses were recorded
by a standard method on a Dionex UItiMate 3000 HPLC
instrument using an Agilent Extend-C18 column (250 mm × 4.6
mm, 5 μm), 30 °C, 1 mL/min, 240 nm, 30 min. Mobile phase: A
(0.1% phosphoric acid solution), B (acetonitrile). The initial
gradient started with 30% of B, and at 15 min it was up to 70%;
the ratio was maintained until 22 min. Then B was decreased to
30% at 23 min and continued to 30 min. Compound 3 was
prepared according to the literature procedure in 84% overall
yield;4 mp 199.7−200.1 °C (lit mp 197−198 °C4). Pd/C was
OURCHEM (China), 10% content, H2O ≤ 1.0%. Raney-Ni was
Energy Chemical (China), Ni ≥ 90%, 50 μm (water seal), used
directly without additional wash. Pt/C was Energy Chemical,
10% on carbon, 55% water. Raney-Co was Aladdin, 50 μm (water
seal). Other materials, solvents, and reagents were of commercial
origin and used without additional purification.
Triethylammonium 2-Acetyl-6-nitrobenzoate (Triethyl-
ammonium Salt of 3). Compound 3 (321.2 g, 1.54 moL) was
added to toluene (1600 mL), and then triethylamine (170.8 g,
1.69 moL) was added. The reaction mixture was heated to 50 °C
for 3 h. After cooling to 0 °C, the product was filtered off, washed
with toluene (100 mL, 0−5 °C), and then dried under vacuum at
D
DOI: 10.1021/acs.oprd.7b00177
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.7b00177.
■
S
1H NMR, 13C NMR, MS spectra for compounds 1, 2, 4;
reaction process data related to Raney-Ni for reduction of
triethylammonium salt of 3 to prepare 2 (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: zhangfuli1@sinopharm.com.
■
ORCID
Zhong Li: 0000-0002-6498-7241
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Engineering Research Center for Improvement &
Industrialization of Pharmaceutical Processes for financial
support.
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DOI: 10.1021/acs.oprd.7b00177
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