Organic Process Research & Development
Article
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tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (3) (2.52 kg,
12.78 mol) in 2-MeTHF (52.44 L) was added 1-bromo-2-
fluoro-4-iodobenzene (20) (3.56 kg, 11.62 mol) at ambient
temperature. The resultant mixture was heated to 70−75 °C
and maintained at that temperature under stirring until
complete conversion was confirmed by HPLC. The reaction
mixture was cooled to 25 °C and quenched with water (17.48
L). The aqueous layer was discarded. To the organic layer was
charged sodium carbonate (5.57 kg, 52.28 mol) and water
(31.45 L). After degassing with nitrogen, to the resultant
reaction mass were added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)isoxazole (9) (2.93 kg, 12.78 mol) and
tetrakis(triphenylphosphine)palladium (Pd-101) (0.67 kg, 0.58
mol), and the mixture was heated to 50 °C for 15 h and then 70
°C for 5 h. The reaction completion was confirmed by HPLC.
The reaction mixture was cooled to 25 °C and concentrated
under reduced pressure, and the product was crystallized by
addition of n-heptane (34.96 L) and isolated by filtration. This
product was formed as a mixture of rotamers. 1H NMR
(DMSO-d6, 400 MHz): δ 1.38−1.41 (br, 9H), 2.08−2.15 (m,
2H), 2.24 (s, 3H), 2.42 (s, 3H), 3.35−3.57 (m, 4H), 5.18 (s,
1H), 6.93 (d, 1H, J = 8 Hz), 7.15 (s, 1H), 7.66 (d, 1H, J = 8
Hz). 13C NMR (DMSO-d6, 100.6 MHz): δ 10.35, 11.30, 28.10,
30.09, 30.90 (rotamer), 43.68, 43.94 (rotamer), 50.93, 51.17
(rotamer), 76.88, 77.76 (rotamer), 78.47, 111.45, 115.22,
115.86, 123.01, 130.76, 133.46, 153.52, 158.06, 165.43. DEPT
NMR (DMSO-d6, 100.6 MHz): δ 10.36, 11.30, 28.08, 30.09,
30.90 (rotamer), 43.68, 43.94 (rotamer), 50.93, 51.17
(rotamer), 76.86, 77.75 (rotamer), 115.84, 123.00, 133.46.
HRMS calcd for C20H26BrN2O4 (M + H)+: 437.1070, found
yield. This product was formed as a mixture of rotamers. H
NMR (DMSO-d6, 400 MHz): δ 1.34 (s, 9H), 2.23−2.28 (m,
5H), 2.45 (s, 3H), 3.38−3.62 (m, 4H), 5.22 (s, 1H), 6.89−6.94
(m, 1H), 7.04−7.08 (m, 2H), 7.3 (br, 1H), 7.70−7.75 (m, 2H),
7.83 (s, 1H), 10.95 (s, 1H). 13C NMR (DMSO-d6, 100.6
MHz): δ 10.49, 11.40, 28.02, 30.39, 31.21 (rotamers), 43.84,
44.13 (rotamers), 50.61, 50.99 (rotamers), 76.34, 77.20
(rotamers), 78.38, 111.77, 114.10, 114.34, 115.61, 122.00,
125.12, 127.19, 128.94, 150.33, 152.03, 153.72, 154.37, 158.19,
165.22, 167.02. DEPT NMR (DMSO-d6, 100.6 MHz): δ 10.51,
11.41, 28.01, 30.39, 31.21 (rotamers), 43.85, 44.14 (rotamers),
50.60, 50.98 (rotamers), 76.33, 77.18 (rotamers), 114.06,
114.32 (rotamers), 120.88, 121.70, 121.80 (rotamers), 127.14.
HRMS calcd for C26H31N5NaO6S (M + Na)+: 564.1893, found
564.1844. [α]25 +44.20 (c 0.5, DMSO).
D
AZD3264 (1). A stirred solution of tert-butyl (3S)-3-[2-(4-
carbamoyl-5-methyl-2-thienyl)-5-(3,5-dimethylisoxazol-4-yl)-
phenoxy]pyrrolidine-1-carboxylate (16) (2.65 kg, 4.63 mol) in
tetrahydrofuran (25 L) was subjected to clear filtration to
remove the heterogeneous particles at 25 °C. The filtrate was
swapped with 2-propanol to prepare a solution of the reactant
in 13.3 L of 2-propanol. To this mixture was added water
(12.54 L) followed by aqueous HCl solution (11 M in water,
0.84 L, 9.26 mol) at 25 5 °C, and the mixture was heated to
65 5 °C until complete conversion was confirmed by HPLC.
The reaction mass was basified with the ammonia solution
(25% w/w in water, 3.34 L, 46.29 mol) and diluted with water
(7.5 L), and the precipitated mass was stirred and filtered to
obtain the title compound in 91% yield.
Purification. To a stirred suspension of crude AZD3264
(1) (1.75 kg, 3.98 mol) in methanol (23.75 L) and water (2.64
L) was added formic acid (0.24 kg, 5.18 mol), and the mixture
was heated to 40 °C for 1.5 h, cooled to 25 °C, and basified
with aqueous ammonia (12.29 M in water, 1.62 L, 19.92 mol).
437.1026. [α]25 −4.60 (c 0.5, DMSO).
D
tert-Butyl (3S)-3-[2-(4-Carbamoyl-5-ureido-2-thienyl)-
5-(3,5-dimethylisoxazol-4-yl)phenoxy]pyrrolidine-1-car-
boxylate (16). A stirred solution of tert-butyl (3S)-3-[2-
bromo-5-(3,5-dimethylisoxazol-4-yl)phenoxy]pyrrolidine-1-car-
boxylate (22) (2.04 kg, 4.11 mol) and tri-isopropyl borate (2.37
kg, 12.33 mol) in tetrahydrofuran (14.40 L) was cooled to −75
°C. To the above mixture was slowly added n-hexyllithium
(33.00%w/w solution in THF, 2.15 kg, 6.99 mol) while the
temperature of the reaction mass was maintained below −65
°C. The reaction completion was confirmed by HPLC. The
reaction mass was diluted with 2-MeTHF (18.00 L) and
quenched with aqueous dilule HCl (1 M, 24.66 L, 24.66 mol).
The organic layer containing [2-[(3S)-1-tert-butoxycarbonyl-
pyrrolidin-3-yl]oxy-4-(3,5-dimethylisoxazol-4-yl)phenyl]-
boronic acid (23) was concentrated to 11.45 L, and 5-bromo-2-
ureido-thiophene-3-carboxamide (6) (0.88 kg, 3.29 mmol),
potassium carbonate (0.86 kg, 6.16 mol), and water (1.98 L)
were added. After degassing of the resultant mixture with
nitrogen, Pd-118 catalyst (0.05 kg, 0.08 mol) was added, and
the mixture was heated to 35 °C. The reaction was monitored
by HPLC. The product was crystallized by adding excess of
water at 50 °C. After the reaction mass cooled to the room
temperature, the product was isolated by filtration.
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The product was isolated by filtration. H NMR (DMSO-d6,
400 MHz): δ 1.92−2.10 (m, 2H), 2.28 (s, 3H), 2.46 (s, 3H),
2.75−2.82 (m, 1H), 3.00−3.12 (m, 3H), 5.11−5.12 (m, 1H),
6.90 (br, 2H), 7.00−7.03 (m, 2H), 7.30 (br, 1H), 7.70−7.72
(m, 2H), 7.83 (s, 1H), 10.93 (s, 1H). 13C NMR (DMSO-d6,
100.6 MHz): δ 10.54, 11.42, 32.94, 45.51, 53.00, 79.37, 111.76,
114.17, 115.66, 120.70, 121.20, 122.77, 125.39, 126.92, 128.84,
150.12, 152.54, 154.50, 158.13, 165.14, 167.06. DEPT NMR
(DMSO-d6, 100.6 MHz): δ 10.54, 11.43, 32.94, 45.51, 53.01,
79.35, 114.17, 120.70, 121.20, 126.92. HRMS calcd for
C21H24N5O4S (M + H)+: 442.1543, found 442.1554. [α]25
D
−13.80 (c 0.5, DMSO)
ASSOCIATED CONTENT
* Supporting Information
■
S
HPLC and UHPLC methods for AZD3264 and intermediates.
This material is available free of charge via the Internet at
AUTHOR INFORMATION
Corresponding Author
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Palladium Scavenging of 16. A solution of tert-butyl
(3S)-3-[2-(4-carbamoyl-5-ureido-2-thienyl)-5-(3,5-dimethyli-
soxazol-4-yl)phenoxy]pyrrolidine-1-carboxylate (16) (2.89 kg,
4.90 mol) and Quadrasil MP (1.45 kg, 16.04 mol) in 2-
butanone (43.40 L) was heated to 70 °C for 5 h. The resultant
reaction mixture was cooled to 30 °C and filtered through
Celite bed to remove quadrasil and undissolved matter. The
filtrate was concentrated to 14.45 L, crystallized by addition of
n-heptane (28.93 L), and filtered to isolate the product in 94%
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We thank the management team of AstraZeneca for timely
support.
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dx.doi.org/10.1021/op500105n | Org. Process Res. Dev. 2014, 18, 646−651