JOURNAL OF CHEMICAL RESEARCH 2015 453
40–50oC to give 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde (5)
(0.154 g, 82%); m.p. 92–93oC (lit.20 93oC) 1H NMR (400 MHz, CDCl3)
δ 11.48 (s, 1H), 9.55 (s, 1H), 3.02–2.43 (m, 2H), 1.70 (d, J = 15.3 Hz,
2H), 1.41–1.22 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 177.7, 154.9, 142.0, 125.8, 29.8, 28.6, 22.2, 13.6. HRMS calcd
for C14H10ON2Cl 186.0560, found 186.0553.
avoided. This new synthetic route of losartan is important, as a
novel design route, using cheap raw materials, and convenient
workup.
Experimental
All chemicals were purchased from J&k Chemical, Energy Chemical
and Sinopharm. All the solvents were of analytical grade and used
without further purification. TLC was used to check the purity of the
as-synthesised compounds. NMR spectra were recorded on a Varian
INOVA-400 MHz spectrometer. HRMS were recorded on MAT 95 XP
produced by the Thermo Finnigan Company. Thermal analysis was
carried out on XT-4 binocular microscope melting point apparatus, .
2-Cyano-4’-methylbiphenyl (2): A 1000 mL bottle containing
o-chlorobenzonitrile (137.6 g, 1.0 mol), anhydrous manganese
chloride (12.6 g, 0.1 mol), and chlorotrimethylsilane (10.8 g, 0.1
mol) was stirred at –5–0°C in anhydrous THF (200 mL) under
nitrogen, and the prepared p-methylphenylmagnesium chloride
was added over 1 h. The mixture was stirred at 25°C for 8 h and
poured into concentrated hydrochloric acid to bring the pH of the
solution close to 2. The mixture was extracted with ethyl acetate.
The organic phase was washed with water, and dried over anhydrous
MgSO4. The solvent was removed at reduced pressure. The resulting
residue was purified by silica gel column chromatography to
provide 2-cyano-4’-methylbiphenyl (2) as a white solid (166.3 g,
86%). We have investigated the influence of different molar ratio of
p-methylphenylmagnesium chloride/o-chlorobenzonitrile and the
amount of catalysts on the yield. The results are shown in Tables 1 and
2. M.p. 47–48 oC(lit.18 49 oC) 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J =
7.7 Hz, 1H), 7.63 (td, J = 7.7, 1.3 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.47
(d, J = 8.1 Hz, 2H), 7.42 (td, J = 7.7, 1.2 Hz, 1H), 7.31 (d, J = 7.9 Hz,
2H), 2.43 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ 21.2, 111.2, 118.8,
127.2, 128.6, 129.4, 129.9, 132.7, 133.7, 135.2, 138.7, 145.4. HRMS
calcd for C14H11N 193.0891, found 193.0889.
2-Cyano-4’-bromomethylbiphenyl (3): 2-Cyano-4’-methylbiphenyl
(0.193 g, 1 mmol) was added to a solution containing CCl4 (5 mL, 0.196
g) N-bromosuccinimide (NBS, 1.1 mmol) and azobisisobutyronitrile
(AIBN0.017 g, 0.1 mmol) in a two-necked flask equipped with
a condenser, and then the solution was kept at 80oC for 3 h. The
mixture was cooled to room temperature and it was diluted with ethyl
acetate (10 mL) and washed twice with water (2×10 mL), dried over
anhydrous MgSO4 and evaporated. The residue was purified by silica
gel column chromatography to give 2-cyano-4’-bromomethylbiphenyl
(3) as a white solid (0.249g, 91%); m.p. 120–122oC (lit.19 114.5–120oC)
1H NMR (400 MHz, CDCl3) δ 7.70 (dd, J = 7.7, 0.9 Hz, 1H), 7.59 (td,
J = 7.7, 1.3 Hz, 1H), 7.50–7.42 (m, 5H), 7.39 (td, J = 7.7, 1.2 Hz, 1H),
4.48 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 143.7, 137.3, 137.2, 132.8,
131.9, 129.0, 128.4, 128.2, 126.8, 117.6, 110.2, 31.8. HRMS calcd for
C14H10NBr 270.9997, found 270.9991.
2-Butyl-4-chloro-5-hydroxymethyl-1-{[(2’-cyano)-[1,1’-biphenyl]-
4-yl]-methyl}-1H-imidazole (7): 2-Butyl-4-chloro-1H-imidazole-5-
carbaldehyde (0.185g, 1 mmol) and potassium carbonate (0.230 g, 1.67
mmol) was added to a solution of 2-cyano-4’-bromomethylbiphenyl
(0.299 g, 1.1 mmol) in DMF (5 mL) at room temperature. The resulting
mixture was heated to 40oC for 6 h. After completion of the reaction,
methanol (1.5 g) was added followed by slow, dropwise addition of
sodium borohydride (0.023 g) over 10 min while the temperature was
maintained at room temperature. After completion of the addition,
the mixture was stirred at 40oC for 1 h. Distilled water was added to
quench the excess sodium borohydride, and the resultant mixture was
stirred for 20 min. The precipitated solid was filtered, washed with
water (2×10 mL) and toluene (2×10 mL) to give 2-butyl-4-chloro-
5-hydroxymethyl-1-{[(2’-cyano)-[1,1’-biphenyl]-4-yl]-methyl}-1H-
imidazole (7) (0.369 g, 93%); m.p. 158–159oC (lit.17 159–160oC)
1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.7 Hz, 1H), 7.58 (t, J = 7.7
Hz, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 13.7 Hz, 2H), 7.06 (d,
J = 8.1 Hz, 2H), 5.22 (d, J = 10.8 Hz, 2H), 4.45 (d, J = 9.2 Hz, 2H),
2.59–2.46 (m, 2H), 1.67–1.50 (m, 2H), 1.25 (q, J = 13.8 Hz, 2H), 0.81
(t, J = 7.3 Hz, 3H).13C NMR (101 MHz, CDCl3) δ 147.7, 132.8, 131.9,
128.9, 128.4, 126.8, 125.2, 117.5, 110.2, 52.2, 46.2, 28.7, 25.7, 21.4, 12.7.
HRMS calcd for C22H22ON3Cl 379.1451, found 379.1432.
Losartan (8): Sodium azide (82 mg, 1.25 mmol) and zinc
trifluomethanesulfonate was added to a solution of 2-butyl-4-chloro-
5-hydroxymethyl-1-{[(2’-cyano)-[1,1’-biphenyl]-4-yl]–methyl}-
1H-imidazole (7) (0.190 g, 0.5 mmol) in water at room temperature.
The resultant mixture was heated to 100°C and maintained at this
temperature for 6 h. The resulting precipitated solid was filtered and
washed with water. The crude product was dissolved in acetone at
room temperature and then heated under reflux for 1 h, and then
cooled to room temperature. The resultant reaction mixture was
stirred at room temperature for 2h, during which a crystalline solid
was formed. The crystals were filtered, washed with acetone, and
dried under vacuum at 50–60°C to afford 0.192 g (91%) of the title
compound losartan (8); m.p. 183.5–184.5oC (lit.17 184.3–186oC)
1H NMR (400 MHz, DMSO) δ 7.95 (d, J = 7.6 Hz, 1H), 7.79 (t, J = 7.7
Hz, 1H), 7.65–7.51 (m, 4H), 7.24 (d, J = 8.1 Hz, 2H), 5.35 (s, 2H), 5.28
(t, J = 5.2 Hz, 1H), 4.37 (d, J = 5.2 Hz, 2H), 3.34 (s, 2H), 1.56–1.37
(m, 2H), 1.33–1.14 (m, 2H), 0.79 (t, J = 7.3 Hz, 3H). HRMS calcd for
C22H23ON6Cl 422.1622, found 422.1718.
The authors acknowledge financial support from the National
Natural Science Foundation of China (no. J1210040) and the
Hunan Natural Science Foundation (no. 2015JJ4018).
2-Butyl-4-chloro-1H-imidazole-5-carbaldehyde (5): Valeronitrile
(0.83 g, 10 mmol) and methanol (4 g) were added to the flask, then
o
acetyl chloride (1.18 g, 15 mmol) was added dropwise at 0 C. After
2 h, the valeronitrile was completely reacted. The mixture was to pH
= 9 by adding sodium hydroxide solution. The aqueous phase was
extracted with toluene and the organic phases were combined. Then,
methanol (4 g), sodium methoxide (0.030 g), glycine (0.825 g) were
added and the resulting solution was stirred at 0oC for 2 h. After
filtration of the mixture, the resulting white solid was washed with
cold toluene and dried under reduced pressure at 40–50oC to give
N-carboxymethyl pentamidine. Then, POCl3 (0.431 g, 2.8 mmol) and
DMF (0.219 g, 3 mmol) was added dropwise to a flask containing
N-carboxymethyl pentamidine (0.158 g, 1 mmol) and toluene (5 mL).
The temperature was maintained below 60oC. After the addition, the
reaction mixture was heated to 100oC for 2 h. Then the solution was
cooled, and some cool distilled water and sodium hydroxide solution
was added to adjust the pH to 2. The solution was washed with toluene
(20 mL) and the organic phase was combined. Then the solution was
Received 25 May 2015; accepted 7 July 2015
Published online: 7 August 2015
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