Crystallization-Induced Dynamic Resolution of a Diarylmethylamine toward the Synthesis of a Potent TRPM8 Inhibitor

Article abstract of DOI:10.1021/acs.oprd.6b00162

The development and demonstration of a crystallization-induced dynamic resolution (CIDR) to prepare a chiral diarylmethylamine, a key intermediate toward the synthesis of a potent TRPM8 inhibitor, is described. Essential to the development of this process was the discovery of (1) efficient classical resolution conditions by a high-throughput screening method, (2) formaldehyde as the optimal racemization agent based on comparison of first-order reaction rate constants, and (3) mechanical grinding as a method to improve solid-liquid mass transfer and facilitate reaction progress. Kinetic analysis of the racemization process and identification of the substrate functional group required for racemization provided the foundation for a mechanistic proposal.

Full text of DOI:10.1021/acs.oprd.6b00162

Article
pubs.acs.org/OPRD
Crystallization-Induced Dynamic Resolution of a Diarylmethylamine
toward the Synthesis of a Potent TRPM8 Inhibitor
Matthew G. Beaver,* Neil F. Langille, Sheng Cui, Yuan-Qing Fang, Matthew M. Bio,
Matthew S. Potter-Racine, Helming Tan, and Karl B. Hansen
Process Development, Amgen, Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States
S
* Supporting Information
ABSTRACT: The development and demonstration of a crystallization-induced dynamic resolution (CIDR) to prepare a chiral
diarylmethylamine, a key intermediate toward the synthesis of a potent TRPM8 inhibitor, is described. Essential to the
development of this process was the discovery of (1) efficient classical resolution conditions by a high-throughput screening
method, (2) formaldehyde as the optimal racemization agent based on comparison of first-order reaction rate constants, and (3)
mechanical grinding as a method to improve solid−liquid mass transfer and facilitate reaction progress. Kinetic analysis of the
racemization process and identification of the substrate functional group required for racemization provided the foundation for a
mechanistic proposal.
hiral nonracemic amines are integral building blocks for
the synthesis of biologically active molecules. Highlighted
by the commercial success of cetirizine 1 and solifenacin 3,
diarylmethylamines (e.g., 1−3, Figure 1) represent a privileged
A recent project required a practical stereoselective synthesis
of amine 2, an intermediate used in the production of a potent
TRPM8 inhibitor. An evaluation of the current technologies
available for synthesis of the chiral diarylmethylamine motif
identified CIDR as the ideal approach toward this target
molecule. Two criteria must be satisfied for the design of a
successful CIDR: the development of (1) a crystallization
system that resolves the molecule and (2) conditions that allow
its simultaneous epimerization. In the course of process
development, these two conditions may be developed
independently; however, the most critical and challenging
design element involves the combination of these individual
components such that the two processes can proceed effectively
in one-pot with practical efficiency.
C
Figure 1. Diarylmethylamine motif in pharmaceutically relevant
We envisioned that classical resolution of amine 2 could be
achieved based on the precedence established for related
diarylmethylamines in which chiral acids were employed as the
stoichiometric resolving agent.4,8 Toward the development of a
resolution method, a panel of chiral acid resolving agents and
solvent systems were investigated by a high-throughput
screening method;9,10 these experiments identified L-dibenzoyl
tartaric acid (L-DBTA) as the optimal resolving acid in
combination with MeCN/water (95:5) as the solvent system.
In a representative reaction, a solution of L-DBTA in MeCN/
water was added dropwise to a solution of racemic amine 2 in
MeCN/water (95:5) at 20 °C (Scheme 1). After aging
overnight, the desired (S)-amine·L-DBTA 4 was obtained as a
white crystalline solid in 39% yield with 90% de in a single
crystallization. The resulting product purity aligned with our
specifications for amine 2 (≥90% ee) in early development.
Modulating the pKa of an α-amine stereocenter by formation
of the corresponding iminium ion has proven to be an effective
strategy for the racemization of amino acids and related α-
amino carbonyl compounds.6a To identify a suitable iminium
structures.
structure class, which remain an active area of investigation in
drug discovery for a wide range of indications.1 In the context
of cetirizine, numerous stereoselective chemical methods,2 in
addition to approaches utilizing chiral chromatography,3 have
been developed for its large-scale synthesis. Despite these
important advances, classical resolution4,5 remains the preferred
method for the commercial manufacture of diarylmethyl amines
due to the facile synthesis of racemic amine starting materials,
low cost, and ready availability of appropriate resolving agents,
straightforward isolation of the crystalline products, and
opportunities for enrichment of chiral purity through
recrystallization. To surmount the limitation of a 50%
theoretical maximum yield inherent to a classical resolution
approach, researchers have explored in situ racemization
methods to convert the entirety of racemic material to desired
product in what is termed a crystallization-induced dynamic
resolution (CIDR).6,7 This manuscript describes the design,
development, and application of a CIDR for the preparation of
chiral diarylmethylamine 2, including the unique role of
formaldehyde as a facile racemization agent and studies to
determine the key elements of 2 that facilitate its epimerization.
Received: May 6, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.6b00162
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DBTA 4 in the presence of formaldehyde. Subjecting (S)-amine
2 in MeCN/water (95:5) to D-DBTA and catalytic HCHO at
65 °C resulted in the formation of (R)-amine·D-DBTA 4 as a
white crystalline solid with 94% de after 20 h (Scheme 2).
Scheme 1. Classical Resolution of Racemic Amine 2 To
Provide (S)-Amine·L-DBTA 4
Scheme 2. Conversion of (S)-Amine 2 to (R)-Amine·D-
DBTA via CIDR
ion in this setting, kinetic studies of the catalytic racemization
of optically enriched (S)-amine 2 in MeCN/water were
performed (Figure 2).11 Notably, substitution of the resolving
Thus, formaldehyde serves as a singular additive to the classical
resolution to render the transformation dynamic. In agreement
with the racemization studies illustrated in Figure 2, both alkyl
and aryl aldehyde additives were ineffective for this trans-
formation,12 further demonstrating the unique role of form-
aldehyde in this context.
In the course of process development, inconsistencies were
observed during scale-up from exploratory (<1 g) to
intermediate scale (1−200 g). The racemization rate proved
particularly sensitive to the agitation method, where the use of
overhead stirrers equipped with stir paddles resulted in
extended reaction times and stalling of the chiral resolution.
A direct comparison of reactions performed with a magnetic stir
bar versus an overhead stirrer revealed the agitation method to
be a critical process parameter for the successful CIDR
(Scheme 3). Using otherwise identical conditions, a magnetic
Scheme 3. Impact of Agitation Method on Reaction Progress
Figure 2. Racemization (% ee) of (S)-amine 2 versus time (h) for a
range of aldehyde additives.
acid L-DBTA with acetic acid rendered the system homoge-
neous and allowed an accurate comparison of racemization
rates. These data fit well with a kinetic model of a first order
reversible reaction.11 A range of aldehyde catalysts were
explored using the same substrate concentrations and catalyst
loadings such that reaction rate constants could be extrapolated
and directly compared. These experiments identified form-
aldehyde as the optimal additive to provide appreciable levels of
racemization within a reasonable time period. The preponder-
ance of literature evidence illustrates that electron-deficient aryl
aldehydes are optimal for the racemization of a stereocenter
adjacent to an amine functional group; despite this precedence,
a range of aryl aldehydes were less effective for epimerizing (S)-
amine 2 as compared to formaldehyde. Less sterically
encumbered alkyl aldehydes such as butyraldehyde and
trifluoroacetaldehyde were also not suitable for this purpose.
This study represents the first example of diarylmethylamine
epimerization by activation as an iminium ion and the use of
formaldehyde in this context.
stir bar provided (S)-amine·L-DBTA 4 as a white crystalline
solid with 96% de, whereas an overhead stirrer provided
product with only 88% de. The chiral purity of the reaction
utilizing an overhead stirrer could not be improved with
extended aging of the reaction mixture at 65 °C; only upon
inserting a magnetic stir bar to the stalled resolution was an
increase to 91% de observed (2 h at 65 °C), thus meeting
product specification. We attribute the increased resolution
efficiency to attrition-enhanced dissolution, i.e., particle-size
reduction by mechanical grinding with a magnetic stir bar.13
Wet-milling is a tunable particle−particle collision-based
method for reduction in particle size, which serves as a scalable
analogy to stir-bar based grinding. Envisioning long-term
commercial manufacture of this material, we hypothesized
that a high-shear rotor stator wet-milling procedure might allow
mass transfer rates necessary to affect an efficient CIDR. A
demonstration of the optimized CIDR process utilizing a wet
mill was performed to validate this concept (Figure 3). To 197
g of rac-amine 2 in MeCN/water (95:5) was charged L-DBTA
To verify in this setting that the combination of racemization
and chiral resolution could provide a useful platform for CIDR,
an experiment was conducted in which (S)-amine 2 and mis-
matched D-DBTA were combined to produce (R)-amine·D-
B
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Article
stituents, underwent rapid racemization in the presence of
HCHO in agreement with the results obtained for amine 2. In
contrast, amine 6, which is isoelectronic with amine 2 but
differs only in the position of the pyridine nitrogen, did not
racemize under identical conditions. Substrates 7 and 8, lacking
a pyridine ring or aryl substituent, respectively, also did not
racemize. These data demonstrate that both the presence and
position of the pyridine nitrogen is a critical component of the
racemization mechanism.
The geometric requirement of the pyridine nitrogen
combined with the unique role of formaldehyde prompted us
to consider a different mechanism (Pathway A, Scheme 4) than
Scheme 4. Plausible Pathways for Racemization via Iminium
Ion Formation
that traditionally proposed for epimerization of an amine via
iminium ion formation (Pathway B, Scheme 4).15 Both
pathways A and B could originate from the iminium ion
intermediate 10 formed upon condensation of formaldehyde
with amine 2.16 In pathway A, we propose that nucleophilic
addition of the appropriately positioned pyridine nitrogen
could result in aminal formation followed by tautomerization
and dearomatization to form intermediate 9.17 This pathway
accounts for the increased rate of racemization observed with
formaldehyde relative to other aldehydes investigated as the
iminium ion derived from formaldehyde is 2.58 orders of
magnitude more electrophilic than that derived from
benzaldehyde.18 Further, pathway B is expected to be favored
as the aldehyde additive becomes more electron-deficient,
which is inconsistent with the data described in Figure 2.
An efficient and practical synthesis of (S)-amine·L-DBTA 4
could be achieved through the development and implementa-
tion of a crystallization-induced dynamic resolution. Upon
identifying conditions for a successful classical resolution,
formaldehyde was identified as a singular additive to render the
system dynamic through rapid epimerization of the racemic
diarylmethyl amine. Analysis of the substrate scope and
comparison of reaction rates led to the proposal of a distinct
epimerization pathway, which relies on both the geometric
requirement of an appended pyridine nitrogen and the
electrophilic nature of formaldehyde.
Figure 3. Profiling of the chiral purity of amine 2 versus time (t0 = end
of DBTA addition). Microscope image (100×) illustrates particle size
at t = 10 h.14
(0.05 equiv) then HCHO (10 mol %) at 20 °C. Upon
formation of a white slurry, wet milling was commenced, the
reaction temperature was increased to 60 °C, and a solution of
L-DBTA (1.05 equiv) in MeCN/water (95:5) was added
dropwise over 3.5 h. The slurry was aged for an additional 10 h
at 60 °C with continuous wet milling and monitored off-line to
track the chiral purity of the resultant white crystalline solid.
After 10 h, the reaction mixture was cooled to 20 °C and
filtered to provide 355 g (S)-amine·L-DBTA 4 (83% yield) with
91% de. In contrast to previous studies using only an overhead
stirrer (Scheme 3), utilization of a wet mill enabled isolation of
specification quality material in only 10 h.
Efforts to evaluate the scope of this CIDR process provided
key insight into the epimerization pathway. As a direct
comparison to the racemization studies performed for amine
2 (vide supra, Figure 2), a selection of benzylic amines was
subjected to catalytic HCHO in the presence of AcOH at 65 °C
(Figure 4). Diarylmethylamine 5, which differs only by the
absence of electron-withdrawing groups on the aryl sub-
EXPERIMENTAL SECTION
■
General. All reactions were performed under an atmosphere
of nitrogen under anhydrous conditions, unless otherwise
noted. All solvents and reagents were commercially obtained
and used without further purification. H and 13C nuclear
1
magnetic resonance (NMR) spectra were recorded at ambient
temperature at 500 and 125 MHz, respectively, using a Bruker
AVANCE-500 spectrometer or at 400 and 100 MHz,
respectively, using a Bruker AVANCE-400 spectrometer. The
1H NMR data are reported as follows: chemical shift in parts
per million (ppm) from an internal standard of residual
(CH3)2SO in (CD3)2SO (2.50 ppm) or residual CHCl3 in
Figure 4. Effect of substrate structure on the extent of racemization.
C
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CDCl3 (7.27 ppm) on the δ scale, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet), coupling
constants in hertz (Hz), and integration (H). Chemical shifts of
13C NMR spectra are reported in ppm from the central peak of
(CD3)2SO (39.5 ppm) or CDCl3 (77.0 ppm). Infrared (IR)
spectra were recorded on a PerkinElmer Spectrum 100 FT-IR
spectrometer. High resolution mass spectra (HRMS) were
obtained using Agilent 1100 systems. Optical rotations were
measured using a Jasco P-2000 polarimeter at 589 nm and
calculated using the formula: [α]D = αobs/(l(c/1000)), where c
= (g of substrate/100 mL of solvent) and l = 1 dm. Melting
points were measured by differential scanning calorimetry
(DSC) using a TA Instruments Q200 DSC at 10 °C/min.
Enantiomeric excess was determined by high-performance
liquid chromatography (HPLC) performed on an Agilent 1200
HPLC system equipped with a spectrophotometric detector;
spectra and the details of individual methods are described in
the Supporting Information.
(S)-(3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-
2-yl)methanamine 2. To a white slurry of (S)-(3-fluoro-4-
(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamine
hydrochloride19 (10.8 g, 31.7 mmol) in 2-MeTHF (108 mL)
was added NaOH (79 mL, 1.0 M, 79 mmol), and the reaction
mixture was allowed to stir for 1 h at ambient temperature. The
biphasic mixture was transferred to a separatory funnel and the
layers separated. The organic layer was washed with water (108
mL) and brine (2 × 54 mL) and then concentrated in vacuo.
The resultant oil was filtered through a medium-porosity glass-
fritted funnel to remove residual inorganic solids, and the filter
cake was rinsed with a minimal amount of MeCN. The solution
1205 cm−1; HRMS (ESI-TOF) m/z calcd for C13H10F5N2O (M
+ H)+ 305.0708, found 305.0701.
(S)-(3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-
2-yl)methanamine (2R,3R)-2,3-Bis(benzoyloxy)succinate 4
(Classical Resolution). To a solution of rac-2 (17.9 g, 58.7
mmol) in MeCN/water [95:5 v/v] (89.3 mL) was added a
prepared solution of L-DBTA in MeCN/water [95:5 v/v] (21.0
mL, 0.10 g/mL, 5.87 mmol) linearly over 30 min, and the
reaction mixture, upon self-seeding, was allowed to age with
stirring for 30 min at ambient temperature. Additional L-DBTA
in MeCN/water [95:5 v/v] (73.6 mL, 0.10 g/mL, 20.6 mmol)
was added linearly over 2 h and the white slurry was allowed to
age with stirring for 3 d at ambient temperature. The slurry was
warmed to 40 °C, aged for 2 h, then cooled linearly to 20 °C
over 2 h.20 The slurry was filtered through a medium-porosity
glass-fritted funnel, and the filter cake was washed with MeCN/
water [95:5 v/v] (53.6 mL) then MeCN (53.6 mL). The filter
cake was dried over vacuum with a nitrogen sweep to provide
(S)-amine·L-DBTA 4 as a white crystalline solid (15.4 g, 39%).
The enantiomeric excess of (S)-amine was determined to be
90% by chiral HPLC (Chiralpak AY-H column, 4.6 mm × 100
mm, 5 μm, eluent: heptane/EtOH/diethylamine = 95:5:0.2 (v/
v), 1 mL/min, 20 °C, 254 nm. tr(minor): 3.9 min, tr(major):
5.1 min): [α]21D − 17 (c 0.35, EtOH); mp (DSC) = 200.16 °C;
1H NMR (500 MHz, (CD3)2SO) 8.52 (d, J = 4.7 Hz, 1H), 7.94
(m, 4H), 7.78 (t, J = 8.8 Hz, 1 H), 7.49−7.66 (m, 9H), 7.35 (d,
J = 8.4 Hz, 1H), 5.91 (s, 1H), 5.68 (s, 2H); 13C NMR (125
MHz, (CD3)2SO) 167.7, 164.7, 156.0 (d, J = 257.8 Hz), 153.3
(d, J = 250.7 Hz), 145.3 (d, J = 5.5 Hz), 144.9 (d, J = 13.6 Hz),
139.7, 135.0 (d, J = 12.0 Hz), 133.5, 129.3, 129.2, 128.7, 125.7
(d, J = 3.8 Hz), 125.0 (d, J = 3.3 Hz), 124.4 (d, J = 16.4 Hz),
124.3, 119.9 (q, J = 258.3 Hz), 117.0 (d, J = 19.6 Hz), 71.5,
51.4; IR (ATR) 3066, 2950, 1710, 1664, 1518, 1263 cm−1;
HRMS (ESI-TOF) m/z calcd for the freebase C13H10F5N2O
(M + H)+ 305.0708, found 355.0701.
(S)-(3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-
2-yl)methanamine (2R,3R)-2,3-bis(benzoyloxy)succinate 4
(CIDR Demonstration). Step 1. To a 5 L jacketed reactor
(20 °C) equipped with an overhead stirrer and thermocouple
was charged rac-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluo-
ropyridin-2-yl)methanaminium chloride (250 g, 88.3 wt %, 648
mmol) then MTBE (2500 mL) to generate a yellow slurry.
Agitation was initiated, and NaOH (1300 mL, 1.0 M, 1300
mmol) was charged in a single portion by addition funnel. The
reaction mixture was allowed to stir for 1 h at ambient
temperature. Agitation was stopped, the layers separated, and
the organic layer was washed with water (2 × 1250 mL). A
constant volume distillative solvent swap to MeCN was
initiated: start conditions = jacket temp: 20 °C, vacuum: 200
Torr; end conditions = jacket temp: 50 °C, vacuum: 160 Torr
[3000 mL total volume MeCN charged]. The MeCN solution
was discharged and then filtered through a medium-porosity
glass-fritted funnel to a cleaned 5 L jacketed reactor to remove
residual inorganic solids.
was concentrated in vacuo to afford 2 as a pale yellow oil (9.52
1
g, 99%): [α]21 + 48 (c 0.80, EtOH); H NMR (500 MHz,
D
(CD3)2SO) 8.41 (d, J = 5.0 Hz, 1H), 7.67 (ddd, J = 10.1, 8.5,
1.3 Hz, 1H), 7.52 (dd, J = 11.7, 2.2 Hz, 1 H), 7.45 (t, J = 7.8
Hz, 1H), 7.37 (dt, J = 8.5, 4.3 Hz, 1H), 7.24 (d, J = 8.3 Hz,
1H), 5.41 (s, 1H), 2.62 (s, 2H); 13C NMR (125 MHz,
(CD3)2SO) 155.9 (d, J = 255.1 Hz), 153.4 (d, J = 249.6 Hz),
150.6 (d, J = 14.7 Hz), 146.9 (d, J = 5.4 Hz), 145.2 (d, J = 5.5
Hz), 133.7 (dq, J = 12.5, 1.6 Hz), 124.1 (d, J = 3.8 Hz), 123.6
(m, 3C), 120.0 (q, J = 257.8 Hz), 115.6 (d, J = 19.1 Hz), 52.9;
IR (ATR) 3075, 2973, 1599, 1507, 1443, 1217 cm−1; HRMS
(ESI-TOF) m/z calcd for C13H10F5N2O (M + H)+ 305.0708,
found 305.0706.
(S)-(3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-
4-yl)methanamine 6. To a white slurry of (S)-(3-fluoro-4-
(trifluoromethoxy)phenyl)(3-fluoropyridin-4-yl)methanamine
hydrochloride (0.33 g, 0.98 mmol) in MTBE (13 mL) was
added NaOH (2.4 mL, 1.0 M, 2.4 mmol), and the reaction
mixture was allowed to stir for 1 h at ambient temperature. The
biphasic mixture was transferred to a separatory funnel and the
layers separated. The organic layer was washed with water (5
mL) and brine (5 mL), filtered through a medium-porosity
glass-fritted funnel to remove residual inorganic solids and then
concentrated in vacuo to afford 6 as a pale yellow oil (0.23 g,
1
76%): [α]21 − 10 (c 0.17, EtOH); H NMR (400 MHz,
Step 2. Agitation was initiated and to the 20 °C solution of
rac-2 in MeCN generated from Step 1 was charged water (94
mL) to achieve a 95:5 MeCN/water (v/v) solution. Separately,
a solution of L-DBTA (255 g, 713 mmol) in MeCN/water
[95:5 v/v] (1104 mL) was prepared. 5% of the prepared L-
DBTA solution (65 mL) was added linearly over 10 min via
syringe pump and self-seeding was observed. Additional seed
[(S)-amine·L-DBTA 4] (8.59 g, 13.0 mmol) was charged and
the white slurry allowed to age for 18 h at 20 °C. Formaldehyde
D
CDCl3) 8.44 (dd, J = 5.1, 0.9 Hz, 1H), 8.40 (d, J = 2.0 Hz, 1H),
7.52 (t, J = 5.6 Hz, 1H), 7.31 (dd, J = 10.8, 1.8 Hz, 1H), 7.26
(m, 1H), 7.20 (m, 1H), 5.52 (s, 1H), 1.78 (s, 2H); 13C NMR
(100 MHz, CDCl3) 157.1 (d, J = 256.2 Hz), 154.5 (d, J = 253.6
Hz), 146.4 (d, J = 5.2 Hz), 143.6 (d, J = 6.1 Hz), 139.9 (d, J =
10.8 Hz), 138.2 (d, J = 24.3 Hz), 135.7 (dq, J = 12.6, 2.2 Hz),
123.9, 122.9 (d, J = 3.0 Hz), 121.7, 120.4 (q, J = 258.9 Hz),
115.8 (19.5 Hz), 51.6; IR (ATR) 3043, 2818, 1601, 1514, 1476,
D
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column, 4.6 mm × 100 mm, 5 μm, eluent: heptane/EtOH/
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.6b00162.
■
S
Complete experimental details, kinetic data and analysis,
and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: mbeaver@amgen.com.
Present Address
Y.-Q.F. and M.M.B.: Snapdragon Chemistry, 85 Bolton St,
Cambridge, Massachusetts 02140, United States.
Notes
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The authors declare no competing financial interest.
(5) Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Keβeler, M.;
ACKNOWLEDGMENTS
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Sturmer, R.; Zelinski, T. Angew. Chem., Int. Ed. 2004, 43, 788−824.
̈
We thank Dr. L. Steven Hollis for valuable discussions and
support with the acquisition and analysis of NMR spectroscopy
data.
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DOI: 10.1021/acs.oprd.6b00162
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Organic Process Research & Development
Article
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1
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(19) (S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)
methanamine hydrochloride was prepared by the approach detailed in
the following patent: Brown, J.; Chen, J. J.; Gore, V. K.; Harried, S.;
Horne, D. B.; Kaller, M. R.; Liu, Q.; Monenschein, H.; Nguyen, T. T.;
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methanamine hydrochloride, used to prepare rac-2, is to be disclosed
separately.
(20) This particular experiment was aged for an extended time period
and heat cycled to monitor solution stability. Typical experiments
achieve equilibrium within ∼1 h at 20 °C.
(21) The batch was cooled to 20 °C and wet milling stopped for a 16
h period overnight. The % de of the solids improved from 83.4 to 85.6
during this 16 h period, demonstrating the requirement for elevated
temperatures and wet milling for an efficient CIDR process.
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DOI: 10.1021/acs.oprd.6b00162
Org. Process Res. Dev. XXXX, XXX, XXX−XXX