10.1002/cmdc.201700783
ChemMedChem
FULL PAPER
bromoacetate (623 mL, 5.6 mol) was added dropwise at an internal
temperature of 20–25°C. The mixture was stirred at RT for 48 h. The
precipitate was filtered off and the filtrate was concentrated and filtered
again. The residue was taken up in ethyl acetate, the mixture was filtered
and concentrated in vacuo and the residue was purified by distillation over
a 30 cm Vigreux column. The product 71 was obtained at a bath
temperature of 140°C, an overhead temperature of 60–115°C and a
pressure of 1-7 mbar. Yield of compound 71: 28% (purity 86%); 1H NMR
(400 MHz, [D6]DMSO): =7.85 (s, 2H), 5.45 (s, 2H), 4.16 (q, 2H), 1.20 (t,
3H) ppm; MS (EI+) m/z: 156 [M+H]+. Compound 70 was obtained as
distillation residue. Yield of compound 70: 440.0 g (50%); 1H NMR
(400 MHz, [D6]DMSO): =8.14 (d, 1H), 7.77 (d, 1H), 5.42 (s, 2H), 4.18 (q,
2H), 1.22 (t, 3H) ppm; MS (EI+) m/z: 156 [M+H]+.
acetal (53.1 kg, 445.6 mol) and stirred at 80 to 86°C for 2 h. Low boilers
formed were distilled off (16 kg of distillate). The mixture was subsequently
cooled to 50°C, acetone (122 kg) was added, the mixture was maintained
at 50°C and undissolved constituents were filtered off hot. The filter cake
was washed once with acetone (19 kg, 50°C). The combined filtrates were
concentrated by distillation (97 kg of distillate), admixed with isopropanol
(47 kg), once again concentrated by distillation at atmospheric pressure
until a temperature of about 83°C had been reached (60 kg of distillate),
cooled to 70°C and admixed with isopropanol (16 kg). The mixture was
inoculated with methyl 3-(dimethylamino)-2-(1H-1,2,3-triazol-1-yl)acrylate
(83, 0.15 kg) and cooled to 0°C over a period of 7 h. After a further hour at
0°C, the mixture was filtered, the filter cake was washed twice with a
mixture, which had been cooled to 0°C, of tert-butyl methyl ether (16 kg)
and isopropanol (16 kg) and dried at 40°C under reduced pressure. Yield:
43.0 kg (76%, based on 1,2,3-triazole); 1H NMR (500 MHz, [D6]DMSO):
=8.10 (d, 1H), 7.78 (d, 1H), 7.67 (s, 1H), 3.55 (s, 3H), 3.4-2.4 (br. s, 3H),
2.4-1.7 (br. s, 3H) ppm; MS (EI+) m/z: 197 [M+H]+.
Ethyl 3-(dimethylamino)-2-(1H-1,2,3-triazol-1-yl)acrylate (73): Ethyl
1H-1,2,3-triazol-1-ylacetate (70, 1.0 g, 6.45 mmol) was heated in
N,N-dimethylformamide diethyl acetal (3.31 mL, 19.34 mmol) overnight at
100°C. After cooling, the mixture was concentrated, and the residue was
purified by means of preparative HPLC (RP-18 column, mobile phase:
acetonitrile/water gradient). Yield: 1.4 g (100%); 1H NMR (400 MHz,
[D6]DMSO): =8.10 (d, 1H), 7.78 (d, 1H), 7.65 (s, 1H), 4.03 (q, 2H), 3.06
(br. s, 3H), 2.10 (br. s, 3H), 1.12 (t, 3H) ppm; MS (EI+) m/z: 211 [M+H]+.
1-[6-(Morpholin-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1H-
pyrazol-5-ol (molidustat, BAY 85-3934, 45): Method A (gram-scale):
Ethyl 3-(dimethylamino)-2-(1H-1,2,3-triazol-1-yl)acrylate (73, 1.98 g,
9.43 mmol) and 4-(6-hydrazinopyrimidin-4-yl)morpholine (78, 1.89 g,
9.70 mmol) were introduced into ethyl acetate (25 mL) and TFA (502 mg,
4.4 mmol) was added at RT. The mixture was stirred under reflux for 18 h,
then cooled to 0-5°C and subsequently stirred for a further 2 h. The solid
formed was filtered off, washed with cold ethyl acetate and dried first in air
and thereafter under a high vacuum. Yield: 2.13 g (71%); 1H NMR
(400 MHz, [D6]DMSO): =8.42 (s, 1H), 8.38 (s, 1H), 8.01 (s, 1H), 7.73 (s,
1H), 7.70 (s, 1H), 3.71–3.65 (m, 4H), 3.57–3.51 (m, 4H) ppm; 13C NMR
(125 MHz, [D6]DMSO): =44.3, 65.6, 85.6, 102.8, 123.7, 132.9, 135.8,
152.4, 154.1, 154.7, 162.0 ppm; IR (KBr): ν˜=3441, 3135–3108, 2965–
2884, 1636–1345, 1257 cm–1; UV/Vis (acetonitrile/water 1:1): λmax (ε)=249
nm (34928 L (mol cm)–1); MS (EI+) m/z: 315 [M+H]+; Anal. calcd for
C13H14N8O2: C 49.7, H 4.5, N 35.7, O 10.2, found: C 49.5, H 4.4, N 35.5,
4-(2-Chloropyrimidin-4-yl)morpholine (76): 4,6-dichloropyrimidine (45.0
g, 302.1 mmol) was initially charged in water (450 mL). Morpholine (26.3
g, 302.1 mmol) was added and the mixture was stirred at 90°C for 16 h.
The mixture was then cooled to 0°C and the precipitate formed was filtered
off. The precipitate was washed once with water (50 mL) and air-dried.
Yield: 51.0 g (85%); 1H NMR (400 MHz, [D6]DMSO): =8.35 (s, 1H), 6.95
(s, 1H), 3.62 (s, 8H) ppm; MS (EI+) m/z: 200 [M+H]+.
4-(6-Hydrazinopyrimidin-4-yl)morpholine (78): Method A (gram-scale):
4-(6-chloropyrimidin-4-yl)morpholine (76, 53.0 g, 0.27 mol) was charged in
ethanol (260 mL). Hydrazine hydrate (132.9 g, 2.70 mol) was added and
the mixture was stirred under reflux for 16 h. The mixture was cooled to
RT and half of the solvent was removed by distillation. The mixture was
then cooled to 0°C and the solid formed was filtered off. The solid was
washed with cold ethanol, initially air-dried and then dried under reduced
pressure. Yield: 35.0 g (68%); 1H NMR (400 MHz, [D6]DMSO): =7.94 (s,
1H), 7.70 (s, 1H), 5.91 (s, 1H), 4.15 (s, 2H), 3.66–3.60 (m, 4H), 3.45–3.37
(m, 4H) ppm; MS (EI+) m/z: 196 [M+H]+. Method B (kilogram-scale): 4,6-
dichloropyrimidine (74, 35.0 kg, 234.9 mol) was suspended in water (82
kg) at 20°C in a stirred vessel, admixed with triethylamine (28.5 kg, 281.6
mol) and more water (5 kg), then cooled to 12°C. Hydrazine hydrate (14.0
kg, 279.4 mol) was subsequently introduced at 12–14°C over a period of
about 1 h. More water (5 kg) was added, the mixture was stirred for another
3 h at 12°C and was then warmed to 20°C. After 16 h at 20°C, sodium
hydrogencarbonate (23.8 kg, 283.3 mol), then morpholine (23.6 kg, 270.9
mol) and water (5 kg) were added. The mixture was heated at a jacket
temperature of 90°C and stirred for 9 h. The solution obtained was cooled
to 70°C and seeded with 4-(6-hydrazinopyrimidin-4-yl)morpholine (78,
0.14 kg), then cooled to 3°C over a period of 5 h. The suspension obtained
was stirred at 3°C for 3 h and filtered in a number of portions in a peeler
centrifuge. The product cake was in each case washed with cold water and
dried at 40°C for about 8 h under reduced pressure in a mixer-dryer. Yield:
32.9 kg (72%).
O
12.6. Method B (kilogram-scale): In a stirred vessel, 4-(6-
hydrazinopyrimidin-4-yl)morpholine (78, 42.0 kg, 215.1 mol) and methyl 3-
(dimethylamino)-2-(1H-1,2,3-triazol-1-yl)acrylate (83, 44.0 kg, 224.2 mol)
were suspended in ethyl acetate (378 kg), admixed with TFA (12.1 kg,
106.1 mol) and heated under reflux (from 78°C to 81°C) at a jacket
temperature of 90°C for 26 h. The suspension obtained was cooled to 0°C,
stirred at 0°C for 1 h and filtered. The filter cake was washed with ethyl
acetate (53 kg) and dried under reduced pressure at up to 45°C. The filter
cake was admixed with a mixture of water (355 kg) and acetic acid (11.7
kg), then suspended and stirred at 50–54°C for 1 h. After cooling to 24°C,
the suspension was filtered. The filter cake was washed first with water (90
kg), then twice with methanol (50 kg each time) and finally dried at 35–
45°C under reduced pressure. Yield: 57.4 kg (85%).
Synthesis of molidustat sodium (84)
Sodium 1-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(1 H-1,2,3-triazol-1-yl)-
1H-pyrazol-5-olate (molidustat sodium, 84): Kilogram scale: In a stirred
vessel, compound 45 (55 kg, 175.0 mol) was suspended in a mixture of
methanol (200 kg) and water (30 kg), admixed with triethylamine (17.8 kg,
175.9 mmol), heated to 60°C, stirred further for about 1 h and filtered hot
to separate off undissolved constituents. The filter cake was washed with
methanol (15 kg, 60°C). Sodium hydroxide solution (18.7 kg, 210.4 mmol,
45% strength) was slowly introduced at 60°C and methanol (5 kg) was
added. Sodium 1-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-
yl)-1H-pyrazol-5-olate (84, 0.12 kg) was added as seed crystals and the
mixture was stirred at 60°C for another 1 h and cooled to 24°C over a
period of about 2 h. The mixture was stirred for 8 h at this temperature,
subsequently cooled to 0°C over a period of about 1 h and filtered in
portions by means of a centrifuge. The filter cake was washed with a
mixture of water (24 kg) and methanol (168\kg) and also methanol (about
23 kg in each case) and dried all together at 40°C under reduced pressure
Methyl
3-(dimethylamino)-2-(1H-1,2,3-triazol-1-yl)acrylate
(83):
Kilogram-scale: In a stirred vessel, methyl bromoacetate (80, 53.7 kg,
351 mol) was added dropwise to a solution of ethyldiisopropylamine
(74.9 kg, 579.5 mol) and 1,2,3-triazole (20 kg, 289.6 mol) in ethyl acetate
(1843 kg) at 35°C over a period of about 2 h in such a way that the internal
temperature was kept at 35 to 37°C. The reaction mixture was
subsequently stirred at 40°C for 8 h. After cooling to 10°C, the suspension
obtained was filtered, the filter cake was washed with ethyl acetate (53.3
kg) and the combined filtrates were concentrated at up to 60°C under
reduced pressure (255 kg of distillate). The evaporation residue (max.
289.6 mol) was admixed at 40°C with N,N-dimethyl formamide dimethyl
1
in a dryer for 8 h. Yield: 57.6 kg (98%); H NMR (500 MHz, [D6]DMSO):
=8.98 (d, J=1.4 Hz, 1H), 8.72 (s, 1H), 8.68 (s, 1H), 8.64 (d, J=1.4 Hz, 1H),
13
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