Organic Process Research & Development
Article
and the reaction monitored by HPLC for consumption of
(S,R,R)-22 (not detected after 1 h). The reaction mixture was
then diluted with H2O (12 L) and agitated, and the layers
allowed to separate. The lower aqueous layer containing
Ipatasertib di-HCl was removed, and the organic layer was
washed with H2O (4 L). The aqueous extracts were combined
and distilled under reduced pressure in order to remove
residual toluene (∼2 L). The aqueous solution was cooled to
20 °C, and CH2Cl2 (14 L) was added. To the biphasic mixture
was slowly added 5 N NaOH (6.3 L) until pH >12 with good
agitation. The layers were allowed to separate, and the bottom
organic layer was removed. The basic aqueous layer was
extracted again with CH2Cl2 (16 L), and the combined organics
were washed with saturated aqueous NaHCO3 (15 kg)
followed by brine (19 kg). The organics were dried over
anhydrous Na2SO4 (2.79 kg) and then filtered. A slurry of
charcoal (0.91 kg, 20 wt%) in CH2Cl2 (1 L) was added to the
filtrate followed by SiliaMetS thiol (1 kg, 20 wt%) and the
mixture maintained at 22 °C for ∼4 h. The mixture was filtered
through a pad of Celite (3.4 kg) and rinsed with CH2Cl2 (12 L)
until no product was observed eluting from the filter. HPLC
weight assay of the filtrate indicated 3.74 kg (8.17 mol) of
Ipatasertib free-base. The free-base solution at 19 °C was slowly
charged with 12 N HCl (0.65 L, 0.96 equiv), and then the
mixture was distilled under reduced pressure to a minimum
working volume (∼10 L). Additional CH2Cl2 (10 L) was
charged to the reactor, and the solution was distilled until water
was no longer observed in the distillate. To the DCM solution
was slowly charged EtOAc (33 L). The mixture was distilled to
a minimum working volume (∼20 L), charged with EtOAc (20
L), and then distilled. EtOAc (15 L) was added to the mixture,
agitated 4 h, and then filtered. The filter cake was rinsed with
EtOAc (12 L), and the solids were dried at ≤70 °C with
nitrogen purge for ∼48 h. The product was discharged from the
filter dryer to give Ipatasertib mono-HCl (3.23 kg, 80% yield)
as an off-white solid. Analytical results: 99.7 A% [0.26% S,R,S-
diastereomer observed)]; impurity 23 (M399) was not
detected (<0.02 A%) [Method 2.2]; ruthenium content by
IPC-AES = 5 ppm; analysis for PF6 anion by CAD-HPLC
resulted in not detected [Method 2.3]; residual solvent = 0.4%
EtOAc; ion chromatography (IC) = 8.5% chloride (1.14 salt
equivalent); DSC = 141 °C; FTIR (neat) 3269 (br OH),
2,6-dihydroxypyrimidine (R)-5 from (R)-MGM. Spectral and
chromatographic data for the key compounds are found in S2.
This material is available free of charge via the Internet at
AUTHOR INFORMATION
Corresponding Author
■
Present Address
§K.L.S.: OPX Biotechnologies Inc., 2425 55th St., Suite 100,
810 Boulder, CO 80301, USA
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the following people for their contributions
to this project: Nik Chetwyn, Derrick Yazzie, Christine Gu,
Tina Nguyen, Ila Patel, Sarah Stowers, Kelly Louie, Venkata
Ravuri, and Bob Garcia, Jr., for analytical support; Beckee
Rogers and Greg Sowell for process chemistry support; Josef
Bencsik and Nick Kallen at Array Biopharma Inc.; and external
collaborators on this project, including Cambridge Major
Laboratories Inc. and Asymchem. We thank Professors Barry
M. Trost, Scott Denmark, Larry E. Overman, and E. J. Corey
and Drs. Trevor Laird and James Zeller for insightful discussion
and suggestions during the early development stages of this
project. Special thanks to Remy Angelaud for editorial
suggestions with this manuscript.
ABBREVIATIONS
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API: Active Pharmaceutical Ingredient
cGMP: Current Good Manufacturing Practice
Boc: tert-butoxycarbonyl
DCM: dichloromethane
Dppp: 1,3-bis(diphenylphosphino)propane
TsDPEN: (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenyl-1,2-
ethanediamine
MsDPEN: (1R,2R)-N-(methanesulfonyl)-1,2-diphenyl-1,2-
ethanediamine
REFERENCES
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1
2961−2865 (N−H stretch), 1637 (CO stretch); H NMR
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4.8 Hz, 2H), 1.26 (d, J = 6.6 Hz, 3H), 1.25 (d, J = 7.0 Hz, 3H);
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ASSOCIATED CONTENT
* Supporting Information
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S
Supporting Information S1 describes the analytical methods
used during the preparation of cyclopentylpyrimidine trans-1,
β2-amino acid (S)-2, and Ipatasertib; Supporting Information
S1 also provides an alternative procedure for the preparation of
M
dx.doi.org/10.1021/op500270z | Org. Process Res. Dev. XXXX, XXX, XXX−XXX