Organic Process Research & Development
Article
NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.81 (s, 1H),
8.41 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.48−7.44
(m, 2H), 7.32−7.26 (m, 3H), 2.69 (s, 3H); 13C{1H} NMR
(100 MHz, DMSO-d6) δ 151.7, 150.0, 147.5, 136.1, 133.8,
130.0, 129.5, 127.8, 125.9, 121.7, 18.6; melting point = 224−
226 °C; HRMS (ESI-TOF) m/z calcd for C13H13N2O2 [M +
H]+ 229.0972, found 229.0961.
D2O) δ 8.87 (s, 1H), 8.22 (d, J = 8.9 Hz, 1H), 7.83 (t, J = 7.5
Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.35−7.29 (m, 2H), 4.48 (s,
2H), 4.24 (br s, 2H), 3.73 (s, 3H), 3.31 (br s, 6H), 2.68 (s,
3H); 13C{1H} NMR (150 MHz, D2O) δ 156.8, 154.2, 153.9,
147.8, 136.3, 136.1, 130.1, 129.4, 128.0, 127.2, 125.5, 125.1,
116.1, 53.5, 50.9, 40.5, 18.2; melting point = 252−254 °C.
ASSOCIATED CONTENT
* Supporting Information
Manufacture of Omecamtiv Mecarbil (1). To a 12 000
L glass-lined reactor were charged 2 (222 kg, 829 mol, 1.0
equiv), 4-HCl (242 kg, 912 mol, 1.1 equiv), tetrahydrofuran
(554 L, 2.5 volumes), acetonitrile (554 L, 2.5 volumes), and
diisopropylethylamine (129 kg, 998 mol, 1.2 equiv). The batch
was heated at 57 °C for 21 h. Water (1109 L, 5.0 volumes) was
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The Supporting Information is available free of charge on the
1
Copies of H and 13C spectra (PDF)
added, maintaining the batch temperature at 55
5 °C,
AUTHOR INFORMATION
Corresponding Authors
followed by seeding with 1 (16.8 kg, 42 mol, 0.05 equiv).
Water (2218 L, 10.0 volumes) was added to the reactor over 3
h. The resulting suspension was cooled to 22 °C and filtered in
an agitated filter dryer. The filter cake was washed with a
mixture of acetonitrile (166 L, 0.75 volumes) and water (499
L, 2.25 volumes) followed by three cake washes of acetonitrile
(3 × 665 L, 9 volumes). The cake was dried under vacuum
(10−50 mbar) with a jacket temperature of 35−40 °C for 17 h.
Omecamtiv mecarbil (1) (287 kg, 82% yield) was isolated as a
white solid with 99.6 wt % purity by HPLC and 99.9 LC area
% purity. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.57
(d, J = 2.3 Hz, 1H), 8.46 (d, J = 2.5 Hz, 1H), 8.03 (t, J = 7.3
Hz, 1H), 7.82 (dd, J = 8.4, 2.6 Hz, 1H), 7.17 (d, J = 8.5 Hz,
1H), 7.09 (t, J = 7.9 Hz, 1H), 7.01 (t, J = 6.8 Hz, 1H), 3.54−
3.60 (m, 6H), 3.31−3.30 (m, 4H), 2.34−2.42 (m, 6H);
13C{1H} NMR (101 MHz, DMSO-d6) δ 155.0, 152.3, 151.9,
151.1. 139.2, 133.6, 127.3, 127.2, 125.8, 124.1, 124.0, 123.8,
122.8, 119.5, 54.5, 52.1, 43.4, 23.2; melting point = 197−202
°C; HRMS (ESI-TOF) m/z calcd for C20H25FN5O3 [M + H]+
402.1941, found 402.1936.
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ORCID
Notes
The authors declare no competing financial interest.
REFERENCES
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(1) Savarese, G.; Lund, L. H. Global Public Health Burden of Heart
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Manufacture of Omecamtiv Mecarbil (1) Dihydro-
chloride Hydrate. 1 (218 kg, 542 mol, 1.0 equiv) was
charged to a 12 000 L glass-lined reactor, followed by water
(333 L, 1.35 volumes) and 2-propanol (566 L, 2.60 volumes).
The slurry was agitated and heated to approximately 40 °C,
whereupon aqueous 6 N HCl (199 L, 1192 mol, 2.2 equiv)
was charged to the slurry, resulting in a colorless homogeneous
solution. The solution was heated to between 55 and 60 °C
and transferred through an in-line filter to a 6000 L glass-lined
reactor preheated to 55 °C. A rinse of the reactor and filter
consisting of 2-propanol (72 L, 0.33 volume) and water (72 L,
0.33 volume) was also transferred to the 6000 L reactor. The
batch was cooled to 45 °C, and omecamtiv mecarbil (1)
dihydrochloride hydrate seed (8 kg, 3.7 wt %) was charged.
The mixture was aged at 45 °C for 0.5 h, and then 2-propanol
(846 L, 3.9 volumes) was added over 3 h. A heat cycle (heating
to 55 °C for 0.5 h followed by cooling to 45 °C over 1 h) was
conducted, and the mixture was agitated at 45 °C for an
additional 2 h. 2-Propanol (1603 L, 7.37 volumes) was added
over 4 h, and the mixture agitated at 45 °C for 1 h and cooled
to 20 °C over 2 h. The batch was recirculated through a wet
mill for three to four batch turnovers to reduce the particle
aspect ratio. The slurry was filtered in an agitated filter dryer,
and the cake was washed twice with 95:5 v/v 2-propanol/water
solution (2 × 435 L, 4 volumes). The cake was dried under
vacuum with a jacket temperature of 35−40 °C. Omecamtiv
mecarbil (1) dihydrochloride hydrate (248 kg, 93% yield) was
isolated as a colorless crystalline solid with 100 wt % purity by
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(5) (a) Caille, S.; Quasdorf, K.; Roosen, P.; Shi, X.; Cosbie, A.;
Wang, F.; Wu, Z.; Neergunda, A.; Quan, B. P.; Guan, L.. WO 2019/
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HPLC and >99.9 LC area % purity. H NMR (500 MHz,
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Org. Process Res. Dev. XXXX, XXX, XXX−XXX