Organic Process Research & Development
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was stirred for 2 h at −8 to −12 °C under nitrogen; thereafter,
the contents were maintained at room temperature for 2 h. The
inorganic salts were filtered and washed with N,N-dimethyla-
cetamide (75 L). The filtrate contains losartan cyanoaldehyde 5
(having HPLC purity ∼80%; losartan cyanoaldehyde isomer
∼5%; PTBN ∼7%; dibromo-PTBN ∼8%). The filtrate was
cooled to −8 to −12 °C under nitrogen. Methanol (150 L) was
added followed by slow, lotwise addition of sodium
borohydride (7.5 kg, 0.198 kmol) in 30−45 min, maintaining
temperature at −8 to −12 °C under nitrogen. After addition,
the contents stirred at room temperature for 1 h. Aqueous
acetic acid (50% w/w, 24 kg, 0.199 kmol) was added in 15−20
min to quench the excess sodium borohydride; this mixture was
stirred for 1 h, water (345 L) was added, and the resultant
reaction mixture was stirred for 2−3 h at 5−10 °C. The
precipitated solid was filtered, washed with water (2 × 190 L),
and then with toluene (2 × 150 L) to obtain crude losartan
cyanoalcohol (6) (∼ 300 kg). The crude 6 was dissolved in
toluene (1800 L) at reflux and then cooled to room
temperature. The resultant reaction mixture was stirred for 2
h, and the crystallized solid was filtered, washed with toluene
(300 L), and dried under vacuum at 50−60 °C to furnish 210
kg (71.2%) of the title compound 6. Purity by HPLC:25 99.8%;
MR: 159−160 °C; IR (KBr, cm−1): 3273.54, 2962.98, 2940.70,
2872.71, 2222.89, 1593.91, 1575.05, 1481.13, 1465.20, 1424.29,
(100 L; 2−5 °C), and dried under vacuum at 50−60 °C to
furnish 91 kg (81.7%) of the title compound 8. Purity by
HPLC:25 99.8%; MR: 184.3−186 °C; IR (KBr, cm−1):
3374.23,2952.47, 2926.14, 2867.82, 1973.78, 1579.25,
1468.81, 1436.75, 1411.42, 1358.06, 1322.74, 1263.54,
1230.22, 1191.20, 1087.22, 1034.89, 1008.04, 996.08, 763.45;
1H NMR (DMSO, 500 MHz, δ): 0.80 (t, 3H), 1.21 and 1.26
(m, 2H), 1.42 and 1.48 (m, 2H), 2.45 and 2.48 (m, 2H), 4.34
(s, 2H), 5.25 (s, 2H), 7.03 and 7.10 (m, 4H), 7.52 and 7.59 (m,
2H), 7.66 and 7.69 (m, 2H); 13C NMR and DEPT (DMSO,
500 MHz, δ): 13.59 (CH3), 21.60 (CH2), 25.78 (CH2), 28.99
(CH2), 46.41 (CH2), 51.34 (CH2), 123.59 (C), 125.25 (C),
125.64 (C, C), 126.25 (CH, CH), 127.80 (CH), 129.11 (CH,
CH), 130.54 (CH), 130.57 (CH), 131.00 (CH), 136.17 (C),
138.44 (C), 141.01 (C), 147.38 (C); MS m/Z (ESI): 423.17
[(MH)+].
2-n-Butyl-4-chloro-5-hydroxymethyl-1-[[(21-(1H-tetra-
zol-5-yl)[1,11-biphenyl]-4-yl]-methyl]-1H-imidazole, Po-
tassium Salt (1) 1. Losartan 8 (70 kg, 0.165 kmol) was
dissolved in preheated methanol (834 L) at 40−45 °C and
cooled to room temperature, treated with carbon (10%), and
washed with methanol (70 L). To this filtrate was added a
solution of potassium hydroxide (assay 85%, 10.58 kg, 0.161
kmol) in methanol (175 L) at room temperature; the mixture
was stirred for 30 min and filtered through 0.22 μm. The
methanol was evaporated completely under vacuum at 35−45
°C to form a residue which was stripped out with acetone (2 ×
140 L) to remove the last traces of methanol. Acetone (210 L)
was added, and this mixture was heated to 58−60 °C for 15−20
min. The resultant reaction mixture was stirred at room
temperature for 2 h and then 2 h at 2−5 °C,; the solid was
filtered, washed with acetone (117 L; 2−5 °C), and dried under
vacuum at 50−60 °C to furnish 72.8 kg (95.3%) of the title
compound 1. Purity by HPLC:25 99.9%; Potassium content:
8.47% w/w (by IC); IR (KBr, cm−1): 3374.23, 2957.18,
2930.14, 2871.51, 1982.46, 1579.66, 1471.86, 1459.70, 1358.05,
1
1251.40, 1011.63, 999.23, 821.70, 777.44, 767.96; H NMR
(DMSO, 500 MHz, δ): 0.79 (t, 3H), 1.20 and 1.27 (m, 2H),
1.46 (q, 2H), 2.53 (t, 2H), 4.40 (d, 2H), 5.30 (t, 1H), 5.36 (s,
2H), 7.25 (d, 2H), 7.56 and 7.77 (m, 4H), 7.77 and 7.94 (m,
1H), 7.95 (d, 1H); 13C NMR and DEPT (DMSO, 500 MHz,
δ): 13.54 (CH3), 21.59 (CH2), 25.79 (CH2), 29.07 (CH2),
46.43 (CH2), 51.39 (CH2), 110.15 (C), 118.42 (C), 125.33
(C), 125.68 (C), 126.62 (CH, CH), 128.21 (CH), 129.0 (CH,
CH), 130.01 (CH), 133.47 (CH), 133.81 (CH), 136.91 (C),
137.66 (C), 143.98 (C), 147.34 (C); MS m/Z (ESI): 380.15
[(MH)+].
2-n-Butyl-4-chloro-5-hydroxymethyl-1-[[(21-(1H-tetra-
zol-5-yl)[1,11-biphenyl]-4-yl]-methyl]-1H-imidazole (Los-
artan) 8. To a solution of losartan cyanoalcohol (6) (100 kg,
0.263 kmol) in a mixture of toluene (200 L) and NMP (58 kg,
0.586 kmol) at 70−75 °C was added sodium azide (51.4 kg,
0.790 kmol) and triethylamine hydrochloride (98.6 kg, 0.717
kmol). The resultant mixture was heated to 98−102 °C for 35
h. and cooled to room temperature. Water (800 L) was
charged, and losartan was extracted as triethylamine salt 7 with
dichloromethane (1 × 700 L; 1 × 300 L). The aqueous layer
containing sodium azide was safely decomposed by adding
sodium nitrite (35.8 kg, 0.519 kmol) and hydrochloric acid
(∼71.6 kg, 0.685 kmol) at 4−10 °C in 1 h (maintaining pH at
∼2.5), and the aqueous layer was drained. The dichloro-
methane layer was treated with carbon and washed with
dichloromethane (100 L). Water (1200 L) was charged into the
organic layer, and the pH was adjusted to 4.0−4.3 with a
solution of hydrochloric acid (assay 35%, 21.6 kg, 0.205 kmol).
The resultant reaction mixture was stirred at room temperature
for 2 h and then for 2 h at 2−5 °C; the precipitated solid was
filtered, washed with dichloromethane (2 × 50 L; 2−5 °C), and
then washed with water (2 × 50 L; 2−5 °C) to obtain losartan
8, crude (∼220 kg). The crude was dissolved in acetone (500
L) at room temperature, then heated to reflux for 1 h, and
thereafter cooled to room temperature. The resultant reaction
mixture was stirred at room temperature for 2 h and then 2 h at
2−5 °C; the crystallized solid was filtered, washed with acetone
1
1260.03, 1188.45, 1094.05, 1008.31, 996.87, 764.02; H NMR
(DMSO, 300 MHz, δ): 0.81 (t, 3H), 1.22 and 1.29 (m, 2H),
1.43 and 1.53 (m, 2H), 2.47 and 2.52 (m, 2H), 4.32 (d, 2H),
5.21 (s, 2H), 5.30 (t, 1H), 6.90 (d, 2H), 7.10 (d, 2H), 7.26 and
7.36 (m, 3H), 7.54 (m, 1H); 13C NMR and DEPT (DMSO,
300 MHz, δ): 13.7 (CH3), 21.7 (CH2), 25.8 (CH2), 29.1
(CH2), 46.5 (CH2), 51.3 (CH2), 125.3 (C), 125.3 (CH, CH),
125.6 (C), 126.7 (CH), 127.3 (CH), 129.4 (CH, CH), 130.1
(CH), 130.5 (CH), 132.5 (C), 134.6 (C), 139.9 (C), 141.1
(C), 147.3 (C), 160.7 (C); MS m/Z (ESI): 423.17 [(MH)+],
461.1 [(MH)+K].
AUTHOR INFORMATION
■
Corresponding Author
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to colleagues in the Analytical Research
Department of APL Research Centre, a division of Aurobindo
Pharma Limited, Hyderabad, for their valuable contribution to
this work. We also thank the management for giving us
permission to publish this work.
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dx.doi.org/10.1021/op300179u | Org. Process Res. Dev. XXXX, XXX, XXX−XXX