Organic Process Research & Development
Article
hydroxyquinoline (5-ChQ) to its corresponding sodium salt 5-
ChQ-Na with 50 wt % NaOH in DMSO, (2) alkylation with
methyl chloroacetate to generate CQC methyl ester after water
removal, and (3) hydrolysis of CQC methyl ester with a
catalytic amount of 0.1 N HCl or 0.1 N H SO to afford CQC
acid in over 90% yield with 98% purity. Recovery and reuse of
DMSO were demonstrated. Each step of the process was
subjected to reactive chemical evaluations by DSC and/or
ARC for identification of potential runaway safety hazards.
The reaction slurry was then heated to 95−100 °C, and 0.1
N HCl (100 mL, 10 mmol) was added over 30 min. The
reaction mixture was allowed to continue to stir at 95−100 °C
11
until the hydrolysis was complete as monitored by HPLC.
After cooling to ambient temperature, the resulting slurry
2
4
was filtered through a fritted filter funnel. The filtrate was used
12
for DMSO recycling. The wet cake was rinsed with deionized
13
water (100 g × 2), suction-dried, and dried at 50−60 °C/1−
2 mmHg to give 44.0 g of CQC acid (91.5% yield, 98.8%
14
1
purity). H NMR (400 MHz/DMSO-d ) δ 13.11 (br, 1H),
6
8
=
=
.97 (d, J = 8.4 Hz, 1H), 8.50 (d, J = 8.4 Hz, 1H), 7.74 (dd, J1
EXPERIMENTAL SECTION
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8.4 Hz, J = 4.2 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.15 (d, J
2
General. All of the reagents were commercially available
and used as purchased without further purification. Unless
otherwise noted, all of the reactions were performed in round-
8.4 Hz, 1H), 4.96 (s, 2H).
Recycling of DMSO from Previous DMSO Filtrate. To
stirring DMSO filtrate obtained from the hydrolysis step above
(229.4 g) was added 50 wt % NaOH solution dropwise at
room temperature until the pH reached 11−12. The resulting
mixture was then subjected to distillation at 70 °C/255 Torr to
1
bottom or jacketed cylindrical flasks under N . H NMR
2
spectra were recorded on a Bruker Ultrashield 400 NMR
spectrometer. Mass spectra were obtained using a Waters
Micromass ZQ mass spectrometer. HPLC analysis was
performed using an Agilent 1260 chromatograph with a
Zorbax Eclipse XDB-C18 column (5 μm, 4.6 mm × 150 mm).
6
0 °C/44−45 Torr to remove water and methanol. After
approximately 105 g of distillate was collected, the remaining
mixture was cooled to ambient temperature. The solids that
precipitated out were filtered and rinsed with fresh DMSO (11
g). The mother liquor was collected as recycled DMSO for use
as the solvent in the next batch.
Mobile phase A was water containing 0.1% H PO , and mobile
phase B was MeCN containing 0.1% H PO . LC program-
3
4
3
4
ming: 0−11 min, 20−20% B; 11−21 min, 20−50% B; 21−26
min, 50−90% B; 26−26.1 min, 90−20% B; postrun
equilibration, 3 min. Other parameters: flow rate, 1.0 mL/
min; column temperature, 30 °C; UV detector, 255 nm.
General Procedure for DSC Testing. A Q2000 differ-
ential scanning calorimeter from TA Instruments was used
either for constant-heating-rate tests (10 °C/min) over the
temperature range from 25 to 400 °C or for isothermal tests.
About 1 mg of sample was sealed within a glass capillary or
ampule with nitrogen or air as the headspace, respectively. The
sealed capillary or ampule had a total internal volume of ∼5 or
AUTHOR INFORMATION
■
*
ORCID
Author Contributions
The manuscript was written through contributions of all
authors. All of the authors approved the final version of the
manuscript.
∼
20 μL, respectively. They were capable of withstanding
pressures of up to 3000 or 1000 psi, respectively, at 400 °C,
preventing the release of any reaction materials, products, or
byproducts.
Notes
The authors declare no competing financial interest.
General Procedure for ARC Testing. An accelerating
rate calorimeter manufactured by Thermal Hazard Technology
was used in this study. A preweighed sample was loaded into a
Hastelloy C ARC cell. The ARC sphere was connected to the
calorimeter lid and purged with nitrogen. The ARC experiment
was performed in heat−wait−search (HWS) mode. A heat step
of 5 °C, waiting time of 20 min, and detection threshold of
ACKNOWLEDGMENTS
The authors thank John Davis and Grant Von Walt for their
support of this project and Qiang Yang for useful discussions.
■
REFERENCES
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0
.02 °C/min were utilized in this study.
Preparation of CQC Acid. To a 500 mL three-neck
round-bottom flask equipped with an overhead stirrer, a
thermometer, and a distillation system under nitrogen
atmosphere were loaded 5-ChQ (35.92 g, 200.0 mmol) and
fresh DMSO (100 mL, ∼109 g) or recycled DMSO (110−120
g, recovered from a previous batch) plus fresh DMSO (20 g).
The reaction flask was heated to 50−55 °C with stirring. A 50
wt % aqueous solution of NaOH (16.80 g, 210.0 mmol) was
added over 30 min via a syringe pump at 50−55 °C. The
resulting mixture was stirred at 55−60 °C for an additional 1 h.
Water was distilled off at 10−15 Torr/55−60 °C until the
(2) A reported example used 1.5−2.0 equiv of 2-chloroacetic acid
salt. See: Shen, Y. Method for preparing 2-(5-chloro-8-quinolinoxy)-
acetic acid. Faming Zhuanli Shenqing 102718706, Oct 10, 2012.
(3) (a) Scheuzger, K. Etherification process for the preparation of 8-
9
residual water level was <0.5 wt %. ClCH CO Me (22.87 g,
2
2
(
hydroxycarbonyl-methyloxy)quinoline derivatives using azeotropic
2
5
20.0 mmol) was added via a syringe pump over 30 min at
5−60 °C. DMSO (2−3 g) was used to flush the syringe
distillation. PCT Int. Appl. WO2002000625, Jan 3, 2002. (b) Gollut,
J.-J. R.; Gayet, A. J. A. Process for the preparation of quinoline
carboxylic acids. PCT Int. Appl. WO2013072376A1, May 23, 2013.
(c) Sharad, R.; Digamber, J. Manufacture of cloquintocet mexyl ester
safener. Indian Pat. Appl. 2006MU01126, July 4, 2008.
tubing in order to push residual ClCH CO Me into the
2
2
reaction mixture. The reaction mixture was stirred at 55−60
10
°C until 5-ChQ was consumed (1−4 h).
F
Org. Process Res. Dev. XXXX, XXX, XXX−XXX