Organic Process Research & Development
Article
NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 4.57 (d, 2H, J =
4.8 Hz), 4.51 (quintet, 1H, J = 5.2 Hz), 4.13 (dd, 1H, J = 8.4,
6.8 Hz), 3.88 (dd, 1H, J = 8.0, 6.0 Hz), 3.66 (s, 3H), 1.35 (s,
3H), 1.30 (s, 3H); 13C NMR (100 MHz, DMSD-d6) δ 165.5
(d, J = 5.8 Hz), 156.4, 154.8 (d, J = 26.4), 152.1, 147.8 (d, J =
248 Hz), 121.8 (d, J = 18.3 Hz), 108.9, 98.0, 72.9, 67.9, 65.7,
29.4, 26.6, 25.2; 19F NMR (376 MHz, DMSD-d6) δ −126.8;
HRMS (QSTAR) (M + H)+ m/z calcd 344.0808, found
344.0799.
J = 8.6 Hz), 6.98 (m, 1H), 5.14 (br s, 1H), 4.83 (br s, 1H), 4.32
(dd, 1H, J = 12.9, 2.5 Hz), 3.76 (m, 1H), 3.67 (dd, 1H, J = 13.1,
12.9 Hz), 3.58 (s, 3H), 3.46 (ddd, 1H, J = 10.9, 5.3, 5.1 Hz),
3.38 (m, 1H); 13C NMR (100 MHz, DMSD-d6) δ 161.3 (d, J =
4.0 Hz), 155.6 (d, J = 22.8 Hz), 154.6 (d, J = 250 Hz), 152.0,
150.6, 134.3 (d, J = 231 Hz), 133.8 (d, J = 7.1 Hz), 133.1 (d, J =
3.0 Hz), 127.8 (d, J = 10.3 Hz), 125.3 (d, J = 7.0 Hz), 123.9 (d,
J = 21.5 Hz), 95.0 (d, J = 4.0 Hz), 87.1 (d, J = 7.8 Hz), 68.0,
63.8, 50.1, 28.8; 19F NMR (376 MHz, DMSD-d6) δ −124.4,
−149.8; MS (M + H)+ m/z calcd 505.0, found 505.0; Form A
was found to have the following peaks in degrees 2θ, rounded
to 2 significant figures (relative intensity): 11.03 (34%), 15.88
(15%), 16.26 (100%), 19.32 (90%), 20.11 (15%), 22.16 (23%),
26.66 (17%), 27.84 (33%), and 30.18 (17%).
4.8. (R)-3-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)-6-
fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido-
[2,3-d]pyrimidine-4,7(3H,8H)-dione (20). To a mixture of
19 (9.3 kg, 27 mol) and 2-fluoro-4-iodoaniline (6.5 kg, 27 mol)
in THF (48.92 L) was added LiHMDS (0.99 M in THF, 47.2
kg, 54 mol) while keeping the internal temperature between −5
and 0 °C. After addition, the reaction mixture was stirred at −5
to 0 °C for 1 h before it was warmed to rt with stirring
overnight. HPLC analysis indicated <2% 19 remaining. A
premixed solution of MeOH/water (9.3 L/9.3 L) was slowly
added at rt. During the addition, a suspension formed. Then 1
N HCl in 1:1 MeOH/water was slowly added while keeping
the internal temperature below rt until the pH was adjusted to
7.5−6.5. The resulting suspension was stirred at rt for 4 h
before filtration. The filter cake was rinsed with water/MeOH
(3v:1v) (3 × 46.2 L). Product 20 was collected as an off-white
solid (13.6 kg, 93% yield, 99% pure) after drying to a water
content of ≤0.30% under vacuum in a Nutsche filter (≤50 °C).
HPLC retention times (Method 4.2.1.): 20 = 21.4 min, 2-
fluoro-4-iodoaniline = 17.6 min; chiral HPLC retention times
(Method 4.2.4.): 20 = 8.6 min, enantiomer of 20 = 7.9 min; 1H
NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.60 (s, 1H),
7.68 (d, 1H, J = 10.4, 2.0 Hz), 7.52 (d, 1H, J = 8.8 Hz), 6.96
(td, 1H, J = 8.8, 6.0 Hz), 4.41 (m, 1H), 4.25 (dd, 1H, J = 13.6,
3.6 Hz), 4.06 (dd, 1H, J = 8.8, 6.4 Hz), 3.98 (dd, 1H, J = 13.6,
7.6 Hz), 3.78 (dd, 1H, J = 9.2, 5.6 Hz), 3.58 (s, 3H), 1.37 (s,
3H), 1.23 (s, 3H); 13C NMR (100 MHz, DMSD-d6) δ 161.1,
155.7 (d, J = 10.1 Hz), 154.3 (d, J = 218 Hz), 150.5, 134.6, (d, J
= 199 Hz), 133.7 (d, J = 7.0 Hz), 133.1, 127.8 (d, J = 8.0 Hz),
125.3, 124.0, 123.8, 109.1, 95.1 (d, J = 4.4 Hz), 87.1 (d, J = 7.3
Hz), 72.2, 66.1, 48.9, 28.8, 26.6, 25.0; 19F NMR (376 MHz,
DMSD-d6) δ −124.5, −149.3; MS (M + H)+ m/z calcd 545.0,
found 545.0.
AUTHOR INFORMATION
Corresponding Author
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Q. Dong, Dr. F. Zhou, Dr. X. Gong, Dr. J. Reddy,
and Dr. K. Goodwill, at Takeda California, Inc. for their helpful
discussions in synthetic route scouting process. We thank Ms.
E. Kolosovsky-Simberg and Dr. L. Zeng at Takeda California,
Inc. for analytical method development work. We thank Dr. B.
Pierson, Ms. D. Chen, and Dr. J. McKiernan at Irix for
analytical method refinements and tests. We thank Dr. J. Studer
and Dr. P. Noblin from TGRD, Drs. Q. McCubbin, F. Hicks,
N. Faiber, Mr. Ian Armitage, and Ms. T. Jiang from Millennium
for analytical methods and scale-up procedures review and
suggestions.
REFERENCES
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4.9. (R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-
4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-
4,7(3H,8H)-dione (TAK-733, 1, Form A). A mixture of 20
(13.6 kg, 25.0 mol), NMP (44.0 L), MeOH (3.45 L), and conc.
HCl (4.08 kg) was heated at 55 °C until a solution was formed.
After stirring at 55 °C for 2 h, HPLC analysis indicated <1% 18
remaining. The reaction mixture went through polish filtration
and was heated back to 55 °C. MeOH (27 L) was added
followed by TAK-733 seed crystals (131 g, Form A). MeOH
(334 L) was slowly added over 3 h. After addition of MeOH,
the resulting suspension was held at 55 °C for 2 h and cooled
down to 0 °C in 4 h. After holding at 0 °C for 9 h, the solid was
filtered and rinsed with MeOH (3 × 60 L). The final API 1 was
obtained as a white solid (10.6 kg, 84% yield, >99% purity)
after drying to a methanol content of ≤3000 ppm and a NMP
content of ≤530 ppm under vacuum in a Nutsche filter drier
(≤50 °C). HPLC retention time (Method 4.2.1.): 15.3 min;
chiral HPLC retention times (Method 4.2.2.): 1 = 4.7 min,
enantiomer of 1 = 3.9 min; chiral purity (>99.5% ee according
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1
to chiral HPLC); H NMR (400 MHz, DMSO-d6) δ 10.24 (s,
1H), 8.52 (s, 1H), 7.69 (dd, 1H, J = 10.4, 1.8 Hz), 7.52 (d, 1H,
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dx.doi.org/10.1021/op300198a | Org. Process Res. Dev. 2012, 16, 1652−1659