Organic Process Research & Development
Article
and the water layer was extracted with toluene (2 × 3.0 L).
The acid water layer was distilled to recycle trifluoroacetic acid
under reduced pressure. The combined organic layer was
washed with 0.45 M Na2CO3 solution to adjust the water
phase to pH = 7.0−8.0, then dried with anhydrous MgSO4,
and concentrated under reduced pressure to obtain the crude
product of N-(4-formyl-2-methylphenyl) pivalamide 9c as a
white solid (538.74 g, 82%). Mp 46.3−48.6 °C. Spectral data:
1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 8.35 (d, J = 8.4
Hz, 1H), 7.73 (dd, J = 10.4, 3.2 Hz, 2H), 7.49 (br s, 1H), 2.34
(s, 3H), 1.35 (s, 9H). 13C NMR (150 MHz, CDCl3) δ 191.43,
176.71, 141.92, 132.25, 131.17, 129.99, 127.27, 120.98, 40.31,
layer was washed with water to adjust the water phase to pH =
7.0−8.0, then dried with anhydrous MgSO4, and concentrated
under reduced pressure to obtain the crude product of N-(2-
methyl-4-(1-methyl-1H-benzimidazol-2-yl) phenyl) butyrimi-
damide 12 as a brown gray solid (436.30 g, 95%). Mp 131.0−
135.5 °C. Spectral data: 1H NMR (400 MHz, CDCl3) δ 7.83−
7.76 (m, 1H), 7.64 (s, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.40−
7.38 (m, 1H), 7.31−7.29 (m, 2H), 6.92 (d, J = 8.0 Hz, 1H),
4.39 (brs, 2H), 3.88 (s, 3H), 2.35 (m, 2H), 2.22 (s, 3H),
1.80−1.79 (m, 2H), 1.08(m, 3H). MS-ESI: m/z 307.2[M +
H]+.
4.6. Synthesis of 1,7′-Dimethyl-2′-propyl-2,5′-bi(1H-
benzimidazole) (1). N-(2-Methyl-4-(1-methyl-1H-benzimi-
dazol-2-yl)phenyl) butyrimidamide 12 (398.06 g, 1.3 mol) and
CH3CN (3.5 L) were added to a 15 L flask, and the mixture
was mechanically stirred for 0.5 h at 5−10 °C. To the mixture
was added a solution of 0.2 M Ca(ClO)2 (187.98 g, 1.3 mol) at
10−15 °C, until the raw materials reacted fully. Then a
solution of 5 M NaOH (160.68 g, 3.9 mol) was added, with
reaction at 15−20 °C for 1 h until the intermediate 13 reacted
completely. The reaction was filtered, washed with MeOH, and
concentrated under reduced pressure to recover the solvent.
The crude product was purified by recrystallization with 50%
EtOH in H2O to afford pure 1,7′-dimethyl-2′-propyl-2,5′-
bi(1H-benzimidazole) 1 as a white solid (324.27 g, 82%).
Purity 99.91% (HPLC). Mp 137.5−139.1 °C. Spectral data:
1H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 7.74 (s, 1H),
7.65 (d, J = 7.5 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.42 (s,
1H), 7.25 (m, 2H), 3.89 (s, 3H), 2.84 (d, J = 7.5 Hz, 2H), 2.58
(s, 3H), 1.83 (q, J = 7.4 Hz, 2H), 1.03−0.92 (t, J = 7.4 Hz,
3H). MS-ESI: m/z 305.2 [M + H]+.
27.72, 17.57. MS-ESI: m/z 242.1 [M + Na]+, 220.1 [M + H]+
.
4.3. Synthesis of N-(2-Methyl-4-(1-methyl-1H-benzi-
midazol-2-yl) phenyl) Pivalamide (10). N-Methyl-o-
phenylenediamine 6 (296.17 g, 2.40 mol) and MeOH (2.0
L) were added to a 5 L flask, and the mixture was mechanically
stirred for 0.5 h under the room temperature. N-(4-Formyl-2-
methylphenyl) trimethylacetamide 9c solid (438.56 g, 2.0 mol)
was added to the mixture, which was then refluxed for 3 h. The
mixture was cooled at 30−40 °C, and saturated NaHSO3
solution (315.30 g, 3.0 mol) was added, followed by stirring for
1 h. The resulting mixture was filtered, washed with MeOH,
and concentrated under reduced pressure to recover the
solvent. The crude product was purified by recrystallization
with 45% EtOH in H2O to afford pure N-(2-methyl-4-(1-
methyl-1H-benzimidazol-2-yl)phenyl) pivalamide 10 as a
white solid (546.04 g, 85%). Mp 175.4−176.1 °C. Spectral
1
data: H NMR (400 MHz, DMSO-d6) δ 9.00 (brs, 1H), 7.73
(d, J = 1.2 Hz, 1H), 7.67−7.64 (m, 2H), 7.61 (d, J = 7.8 Hz,
1H), 7.42 (d, J = 8.2 Hz, 1H), 7.27 (m, 2H), 3.89 (s, 3H), 2.28
(s, 3H), 1.27 (s, 9H). 13C NMR (150 MHz, CDCl3) δ 176.75,
153.58, 143.00, 137.53, 136.72, 131.76, 128.61, 127.73, 126.21,
122.78, 122.50, 122.07, 119.77, 109.69, 40.07, 31.84, 27.81,
17.69. MS-ESI: m/z 322.2 [M + H]+.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
4.4. Synthesis of 2-Methyl-4-(1-methyl-1H-benzimi-
dazol-2-yl) Aniline (11). N-(2-Methyl-4-(1-methyl-1H-ben-
zimidazol-2-yl)phenyl)pivalamide 10 (513.92 g, 1.6 mol),
NaOH (323.23 g, 8.0 mol) and 85% EtOH in H2O (1.2 L)
were added to a 2.5 L flask, and the mixture was mechanically
stirred for 1.0 h at 50 °C, then heated to 95 °C with 3 bar of
pressure, and stirred for 8 h. The mixture was cooled to room
temperature and then evaporated to obtain the crude product.
The crude product was purified by recrystallization with 35%
EtOH in H2O to afford pure 2-methyl-4-(1-methyl-1H-
benzimidazol-2-yl) aniline 11 as a gray solid, (360.39 g,
Optimization study of the hydrolysis reaction, opti-
mization study of the amidation reaction, HPLC spectra
of compound 1, and NMR, MS data for compounds 9c,
AUTHOR INFORMATION
■
Corresponding Author
Jianhong Zhao − Engineering Research Center of
Pharmaceutical Process Chemistry, Ministry of Education,
School of Pharmacy, East China University of Science and
1
95%). Mp 147.4−149.9 °C. Spectral data: H NMR (400
MHz, DMSO-d6) δ 7.59−7.57 (m, 1H), 7.53−7.51 (m, 1H),
7.46 (s, 1H), 7.41 (dd, J = 8.4, 1.6 Hz, 1H), 7.24−7.15 (m,
2H), 6.73 (d, J = 8.4 Hz, 1H), 5.36 (brs, 2H), 3.84 (s, 3H),
2.14 (s, 3H). MS-ESI: m/z 238.1 [M + H]+.
Authors
4.5. Synthesis of N-(2-Methyl-4-(1-methyl-1H-benzi-
midazol-2-yl)phenyl) Butyrimidamide (12). 2-Methyl-4-
(1-methyl-1H-benzimidazol-2-yl) aniline 11 (355.65 g, 1.5
mol) and butyronitrile (418.50 g, 6.0 mol) were added to a 5 L
flask, and the mixture was mechanically stirred for 1.0 h at
room temperature. The mixture was added with AlCl3 (606.15
g, 4.5 mol) at 135−140 °C for 3 h. The mixture was cooled at
85 °C, and DCE (1.5 L) was added, followed by cooling to 0−
5 °C. Then slow addition of 5 M NaOH ice water solution
(742.20 g, 18.0 mol) occurred, with mechanical stirring for 1.0
h. The organic layer was separated, and the water layer was
extracted with DCE (2 × 800 mL). The combined organic
Yicheng Xiong − Engineering Research Center of
Pharmaceutical Process Chemistry, Ministry of Education,
School of Pharmacy, East China University of Science and
Technology, Shanghai 200237, China
Wu-Lin Yang − Engineering Research Center of
Pharmaceutical Process Chemistry, Ministry of Education,
School of Pharmacy, East China University of Science and
Fan Yang − Engineering Research Center of Pharmaceutical
Process Chemistry, Ministry of Education, School of
1026
Org. Process Res. Dev. 2021, 25, 1022−1027