The M?CPbA?NH3(G) system: A safe and scalable alternative for the manufacture of (substituted) pyridine and quinoline N?oxides?

Article abstract of DOI:10.1021/acs.oprd.8b00358

An improved, safe, and scalable isolation process for (substituted) pyridine and quinoline N-oxides in quantitative yields along with high purities using the m-CPBA?NH₃(g) system is described. The safety was assessed by reaction calorimetry and differential scanning calorimetry studies for possible hazards during the conversion and isolation steps. Careful interpretation of the data substantiated the safety and scalability. The process flow is simplified to meet the industrial requirements of safety, cost-effectiveness, and utility minimization. The reaction was safely demonstrated at a 2.5 kg scale.

Full text of DOI:10.1021/acs.oprd.8b00358

Subscriber access provided by Caltech Library
Full Paper
m-CPBA-NH3(g) system: A safe and scalable alternative for
manufacture of (substituted)pyridine and quinoline N-oxides†
Amey Palav, Balu Misal, Anilkumar Ernolla, Vinod Parab, Prashant
Waske, Dileep Khandekar, Vinay Chaudhary, and Ganesh Chaturbhuj
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00358 • Publication Date (Web): 28 Dec 2018
Downloaded from http://pubs.acs.org on January 1, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 25
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
m-CPBA-NH system: A safe and scalable
3
(g)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
alternative for manufacture of (substituted)pyridine
and quinoline N-oxides†
a,b
a,b
a
a
c
Amey Palav , Balu Misal , Anilkumar Ernolla , Vinod Parab , Prashant Waske , Dileep
c
c
b
Khandekar , Vinay Chaudhary , Ganesh Chaturbhuj*
aLoba Chemie Pvt. Ltd., Research, and Development Center, Tarapur, Thane, India 401506
bDepartment of Pharmaceutical Sciences and Technology, Institute of Chemical Technology,
Matunga, Mumbai, India 400019
cMettler-Toledo India Private Limited, Amar Hill, Saki Vihar Road, Powai Mumbai, 400072
1
ACS Paragon Plus Environment

Organic Process Research & Development
Page 2 of 25
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
GRAPHICAL ABSTRACT:
R2
R2
R1
1b-11b
1
a-11a
R1
R1
N
1.m-CPBA, 10-15 °C; 30-35 °C
N
2.Na SO , 30-35 °C
O
2
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R2
R2
3
.NH (g), 10-15 °C
3
R3
2b-14b
R3
R1
N
N
1
12a-14a
O
1
4 examples
2
ACS Paragon Plus Environment

Page 3 of 25
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
ABSTRACT: An improved safe and scalable isolation process for (substituted) pyridine and
quinoline N-oxide with quantitative yield along with high purity products using m-CPBA-NH3(g)
system have been described. The safety was accessed by reaction calorimetry and DSC studies
during conversion and isolation steps for possible hazards. The careful interpretation of the data
substantiates the safety and scalability. The process flow is simplified to meet the industrial
requirement of safety, cost-effectiveness, utility minimization. The reaction was safely
demonstrated at 2.5 kg scale.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
KEYWORDS: Pyridine, Pyridine N-Oxide, m-CPBA, Ammonia.
1. INTRODUCTION
In recent years, the importance of heterocyclic N-oxides is continuously growing in the field of
research and industrial application. The N-oxide scaffold is an integral part of several drug
1
molecules such as tirapazamine, an anticancer, and pyrithione zinc as fungistatic and
2
bacteriostatic. They have also been a promising lead compound in the new drug discovery for
3
4
5,6
7
HIV, cancer, tuberculosis and type II Diabetes. Moreover N-oxide derivatives of substituted
8
pyridine serve as a key raw material for synthesis of rabeprazole and antiulcer, lansoprazole, a
9
proton pump inhibitor. The 2- and 4-substituted pyridine and quinoline N-oxides have a high
10
demand in drug development and are synthesized by Polonovski rearrangement in presence of
1
1
12,13
acetic anhydride or trifluoroacetic acid.
There are several reagents used for the N-oxidation of heterocycles like peracetic acid/AcOH,14
15
16
17
18
perbenzoic acid, monoperpthalic acid, H O /AcOH, H O /[Mn(TDCPP)Cl], H O /MTO,
2
2
2
2
2
2
BTSP/HOReO3,19,20 dimethyl dioxirane. The aforesaid methods have restricted application at
21
2
2
the industrial scale due to safety concerns like explosions at elevated temperatures with the
3
ACS Paragon Plus Environment

Organic Process Research & Development
Page 4 of 25
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
23
decomposition of oxidant and the product. Since N-oxides are highly water soluble, poses
difficulty in isolation and purification during biphasic extractive workup. To scale up N-oxides
manufacture to higher volumes, there arises a need for the development of a simplified process
which meets the industrial requirement of safety, cost-effectiveness, minimizing utilities and
waste.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Safety in the reactions at the manufacturing scale is of utmost importance. The reagent used and
the products are of explosive nature hence necessitate the careful assessment of heat changes and
stability of the chemicals involved at these conditions. The safety studies using reaction
calorimeter and differential scanning calorimetry (DSC) for identifying the onset of degradation
is very much required.
Herein, we report the industrial protocol for preparation of N-oxides of (substituted) pyridine and
quinoline using an organic oxidant. Amongst the many oxidants reported for N-oxidation, m-
CPBA was chosen to use under controlled conditions of solvent compatibility, mode of addition,
the temperature along with scavenging of excess peroxides in the reaction mixture.24,25
2
. RESULTS AND DISCUSSION
In all the initial experiments oxidation step showed the quantitative conversion, the only hurdle
to be tackled was to separate m-chlorobenzoic acid generated during the reaction and N-oxides
from the reaction mixture. The attempts were made to precipitate m-chlorobenzoic acid as a salt
using organic and inorganic bases such as sodium bicarbonate and triethylamine. The salts being
water soluble and insoluble in organic solvents, may be separated from the mixture either by
extractive work up or filtration. Among the bases used, sodium salt resulted in poor yield due to
the considerable water solubility of the product, while triethylammonium salt, did not precipitate
4
ACS Paragon Plus Environment

Page 5 of 25
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
from the reaction solvent which was expected to be filtered. To overcome these complexities,
one more alternative was attempted to convert m-chlorobenzoic acid into its ammonium salt not
by aqueous liquor ammonia but by sparging anhydrous ammonia gas into the reaction mass in an
organic solvent. To our surprise, ammonium m-chlorobenzoate precipitated from the reaction
mixture, which was separated quantitatively by filtration on the Celite bed. Hence there was a
necessity to optimize the aforesaid initial findings to achieve maximum recovery of m-
chlorobenzoic acid and solvent.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
.1 Protocol Development
The experiments were planned to ascertain the effect of chlorinated, hydrocarbons and ester
solvents (Table 1). Although the oxidation preceded smoothly in hexanes and cyclohexane but
posed difficulties of non-filtrable cake of ammonium m-chlorobenzoate which entrapped the
product (Table 1 entries 3 and 4). In addition to this, the hydrocarbon solvents are highly
flammable even with an electrostatic charge. Use of dichloromethane (DCM) gave comparable
yield with the reasonable recovery of solvent while dichloroethane (DCE) with similar results
and better solvent recovery (Table 1 entries 1 and 2) suggested in the literature, that DCM would
2
4
be a choice of solvent for oxidation purpose. But there are certain issues at higher concentration
of m-CPBA in DCM due to intrinsic instability of m-CPBA even though they are compatible.26
However, the chlorinated solvents being ICH class 1 and 2 needs replacement to address the
issues of toxicity, high volatility, and recovery. Hence, the use of environmentally benign ICH
class 3 solvents such as ethyl acetate (EtOAc) and isopropyl acetate (iPrOAc) was desirable.
Both the solvent gave comparable yield and purity of the desired product with better recovery,
while isopropyl acetate was the solvent of choice (Table 1 entries 5 and 6). We also studied the
compatibility of m-CPBA in iPrOAc in which the onset temperature was found to be 50.07 °C
5
ACS Paragon Plus Environment

Organic Process Research & Development
Page 6 of 25
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
which was much lower than the decomposition temperature of m-CPBA 89 °C in solid state and
2
6
heat release of 205.3 J/g (Fig 1). The temperature during the addition and quenching of m-
CPBA is much lower that the onset temperature. Hence, this confirms that m-CPBA does not
react or forms a hazardous combination with iPrOAc.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Fig 1. DSC graph (test range 30-400°C) of 0.3g/mL m-CPBA in iPrOAc.
Table 1. Solvent optimization and recovery studya
Solventb
Yield (%)c
Purity (%)d
Entry
Class
Solvent
Recovery (%)
85-90
1
DCE
1
90.0
95.0
6
ACS Paragon Plus Environment

Page 7 of 25
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
2
3
4
5
6
DCM
2
2
2
3
3
89.0
98.0
98.1
98.0
98.0
95.6
99.0
99.2
96.0
99.8
55-60
62
Hexanes
Cyclohexane
EtOAc
60
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
82-85
90-92
iPrOAc
a
b
Experimental condition: pyridine (200.0 g, 2.5316 mol 1.0 equiv.), 10 vol., 75% m-CPBA (610
c
d
g, 3.53 mol, 1.4 equiv.), Isolated yield, Isolated product purity by GC
The oxidation is known to be an exothermic reaction; to avoid the runaway necessitates the
determination of heat of reaction using reaction calorimeter. Hence, initially, the temperature and
time optimization studies were performed to access the ∆T both during the conversion and
isolation steps (Table 2). As per the protocol of 200.0 g input batch of pyridine, the oxidant m-
CPBA was added in 10 portions, maintaining the temperature of the reaction mass between 10-
15 °C. The temperature was optimized during the addition of m-CPBA and the course the
reaction till completion. The results revealed that it was necessary to maintain the temperature
between 10-15 °C during the addition of m-CPBA, followed by maintaining it to 30-35 °C up to
4
h, this resulted in maximum conversion as well as purity of the product accessed by GC. The
aforesaid protocol was subjected to reaction calorimetric assessment using RC 1 (Mettler Toledo
Inc.) to measure the heat of reaction, adiabatic temperature rise and Stoessel’s criticality class
(
Fig 3a and b). The trends of heat changes indicated by RC 1 during the addition of m-CPBA are
depicted in Fig 2.
Table 2. Time and temperature optimization studya.
7
ACS Paragon Plus Environment

Organic Process Research & Development
Page 8 of 25
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Entry
Temperature (°C)b
Time (h)c
% Conversiond
78.2
2
4
6
2
4
6
2
4
6
1
10-15
82.3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
85.6
85.7
2
3
20-25
30-35
88.7
90.5
98.5
98.5
98.5
aExperimental condition: pyridine (200.0 g, 2.53 mol, 1.0 equiv.), iPrOAc (10 vol), 75% m-
b
c
CPBA (610.0 g, 3.53 mol, 1.40 equiv.). During addition of m-CPBA. After addition of m-
d
CPBA. by GC
Fig 2. RC1 trend of m-CPBA addition (--- Tr; --- Tj; --- qr_rtc; ---Vr; ---Tr-Tj; ---Rt)
8
ACS Paragon Plus Environment

Page 9 of 25
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
As depicted in Fig 2 and 3 the maximum heat rise during the addition of 10 portions of m-CPBA
was 19.4 K with Maximum Temperature of Synthetic Reaction (MTSR) 29.44 °C and Onset of
th
Decomposition Temperature (TD ) 101.5 °C calculated by extrapolation using n order kinetic
2
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
software w.r.t DSC data of reaction mixture, indicating that the reaction is safer even if the
cooling fails, as MTSR is much lower TD limit. The Stoessel’s criticality class is 1for m-CPBA
2
4
addition operation, which is regarded as safe (Fig 3).27
(a)
(b)
Fig 3. (a) Runaway Graph Based on Current Values of m-CPBA addition. (b) Stoessel’s
criticality class for m-CPBA Addition.
2.2 Quenching of excess oxidant and work up procedure:
The oxidation reaction was performed with 1.4 equivalent of commercially available m-CPBA
(75% w/w). There is a possibility of traces of peroxide present at the end of reaction time which
may lead to an explosion. To design hazards-free workup procedure necessitates quenching of
unreacted m-CPBA with suitable scavenger prior to ammonia sparging and evaporation of the
solvent. To accomplish this sodium sulfite, a cost-effective scavenger with no product
contamination was used. Sodium sulfite was added at the completion of the reaction until the test
was negative on MN-Quantofix strip. No heat change was observed during the addition of
9
ACS Paragon Plus Environment

Organic Process Research & Development
Page 10 of 25
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
sodium sulfite. This was followed by sparging anhydrous ammonia gas to convert m-
chlorobenzoic acid into ammonium m-chlorobenzoate. Formation of the ammonium salt is an
exothermic process hence needs to be performed at a lower temperature with control on the
amount and rate of ammonia gas sparging. The rate of gas sparging was optimized to 180-200
mL/min. while maintaining the reaction temperature between 10-15 °C, till the reaction mixture
pH raised to 8-9. This neutralization protocol was studied using reaction calorimeter, RC 1 to
establish the safe handling temperature of a reaction mixture containing explosive N-oxide. The
RC1 trend of ammonia sparging is depicted in Fig 4.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Fig 4. Trend of ammonia sparging (--- Tr; --- Tj; --- qr_rtc; ---Vr; ---Rt)
The data revealed, that the maximum heat rise during addition was 2.3 K with MTSR 12.3 °C
and TD 101.5 °C which also reveals that the maximum temperature even after the cooling
2
4
failure would reach to 53.0 °C (Fig 5a). The Stoessel’s criticality class is 1 for the ammonia
sparging operation, which states the reaction conditions are safe (Fig 5b). The temperature rise
10
ACS Paragon Plus Environment

Page 11 of 25
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
during neutralization is a function of moles ammonia reacting which is controllable by a rate of
sparging.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(a)
(b)
Fig 5. (a) Runaway graph based on current values of ammonia sparging. (b) Stoessel’s criticality
class for ammonia Sparging.
2.3 Isolation of product and regeneration of reagent precursor:
The aforesaid operation follows filtration of ammonium m-chlorobenzoate salt leaving the N-
oxide product in the filtrate. N-oxide was isolated by distillation of the solvent under reduced
pressure (20 mm of Hg) at a temperature not exceeding 50 °C with 90% recovery of isopropyl
acetate. The product purity was 98% by G.C in comparison with the standard. To ascertain the
safety during distillation of solvent containing N-oxide, DSC of the isolated pure product as well
as the product in iPrOAc at concentration 0.1 g/mL was studied. The onset point for pure and
solvent phase was 326.42 °C and 330.18 °C which is a very high limit as compared to operating
temperatures during distillation (Fig 6a and b).
11
ACS Paragon Plus Environment

Organic Process Research & Development
Page 12 of 25
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(a)
(b)
Fig 6. (a) DSC graph of pure pyridine N-Oxide; (b) DSC graph of pure pyridine N-Oxide in
iPrOAc (0.1g/mL).
To recover m-chlorobenzoic acid from the salt, ammonium m-chlorobenzoate (452.4 g) was
dissolved in 4.0 L of demineralized water followed by acidification with 580 mL 20 % HCl,
filtration and drying at 95 °C till constant weight to yield m-chlorobenzoic acid 398.0 g, (96 %
recovery, 99 % purity by HPLC). It is well known in the literature that m-chlorobenzoic acid can
be recycled to m-CPBA.28
Kilo Scale protocol Development:
The RC1 trends revealed that the process can be scaled up in the equipment setup available for
general purpose reactor. We scale up the reaction to 2.5 kg of pyridine input in 50 L glass reactor
with suitable jacketed cooling arrangement and outlet connected to the common scrubber. Initial
addition of pyridine to the isopropyl acetate showed no exothermicity using digital temperature
indicator which substantiates observation in the RC1 experiment. The time taken for the addition
of the first portion of m-CPBA (762.0 g) was 15 min with a temperature rise from 10 °C to 13
12
ACS Paragon Plus Environment

Page 13 of 25
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
°
C. After addition, the reaction mixture was aged for a further 10 min to stabilize to 10 °C. The
same exothermic pattern was observed for subsequent 5 portions of m-CPBA. Further portions
th
th
7 to 10 showed a slight temperature rise of 1 °C. The operational procedure of aging the
reaction mixture for 10 min after each addition of m-CPBA portion was followed even though
the temperature was stabilized quickly. The addition of sodium sulfite also showed no exotherm,
which indicates the complete consumption of m-CPBA. Even the equivalence ratio of m-CPBA
used was 1.4 equiv., (75% w/w), which corresponds to 1.0 equiv. stoichiometrically. The crucial
operation in the scale-up was ammonia sparging, where it can lead to rapid exotherm (Fig 4) but
can be controlled by sparging rate. Based on RC1 data (Fig 4) were a rapid exotherm was
observed at a sparging rate of 180-200 mL/min. Hence, for 2.5 kg input batch, initially sparging
began with a low flow rate of 100-110 mL/min for 1 h. As no rapid exotherm was observed, the
flow rate to 150-180 mL/min for a further 1 h and then to 180-200 mL/min where the similar
exotherm pattern was observed. The filtration of the ammonium 3-chlorobenzoate salt was with
no hurdles like caking or blocking filter pad. During solvent distillation, the thermic fluid bath
temperature was maintained between 45-50 °C with a vacuum of 20 mm of Hg resulted in 90%
solvent recovery and pyridine N-oxide (97% yield, 99.4% purity).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
.4 Scope of reaction
To investigate the scope and generality, the optimized protocol was extended to (substituted)
pyridines and quinolines at the scale of 200.0 g (Table 4). The result reveals that the protocol is
well suited for all the substrates which showed excellent yield and purity. The simplified
schematic process flow is presented in Scheme 1. The DSC study for representative substituted
pyridine N-oxide was also performed using a pure sample as well as a pure sample in iPrOAc,
which ensures the process safety for the scope of reaction. Table 3 reveals the onset data of pure
13
ACS Paragon Plus Environment

Organic Process Research & Development
Page 14 of 25
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
product and heat release. For high energetic substrate 4-(4-nitrobenzyl) pyridine-N-oxide, 10b
both DSC in pure form as well as DSC in iPrOAc was studied at higher concentration. In
solution form, the endotherm was observed, since the product was insoluble at 0.5 g/mL
concentration (refer to supplementary information). The onset for pure sample and in solvent
form was 261.11 °C and 258.89 °C, respectively. which concludes that the isolation step during
the solvent distillation is safe for this molecule.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 3: DSC data for substituted N-oxides
Entry
Substrate
Melting range
°C)
Onset Pure form
(°C)
Heat Release
(J/g)
(
1
1b
3b
65-66
201.19
1302.77
2
38-39
152.01
202.16
140.34
130.12
173.38
208.72
125.64
159.24
971.33
1270.88
1087.53
832.35
457.34
764.86
856.86
882.62
3
4b
183-185
162-163a
92-94
4
5b
5
9b
6
10b
12b
13b
14b
153-155
54-55
7
8
68-69
9
136-138
a
Boiling point
14
ACS Paragon Plus Environment

Page 15 of 25
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
3
. m-CPBA
ammonium 3-chloro
2. Pyridine
NH (g)
3
benzoate salt
1. iPrOAc
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
RBF
. 10-15°C
. 30-35°C
Cool
to
Celite
Filteration
Product
in Solvent
Solvent
recovery
1
2
10-15°C
Isolated
Product
Scheme 1. The process flow for N-oxidation of pyridine.
EXPERIMENTAL SECTION
General Information
All reactions were carried out under the fuming hood. All the chemical and the reagents were
obtained from Loba Chemie with a minimum purity of 99%, m-CPBA (75% w/w) and used as
received. Melting point was recorded on Veego VMP-CM. Thin layer chromatography was done
on pre-coated silica gel plates Kiesegel 60 F254 Macherey-Nagel). Gas chromatography was
performed on Agilent 7890B with BP-5 column (30m X 0.32µm X 0.25 µm), injection
temperature 240 °C, detector temperature 250 °C, initial temperature 100 °C for 2 min hold, final
temperature 250 °C for 2 min hold, flow rate 1.2 mL/min, split ratio 83:1 and runtime 19
minutes. Peroxide content was checked on Macherey-Nagel Quantofix peroxide strips. The rate
of flow of ammonia gas sparging was measured by Agilent ADM flow meter (G-6691-40500).
FTIR spectra were recorded on Thermo Scientific Nicolet IS 5. NMR spectra were recorded on
Agilent MR-400 using CDCl or D O as a solvent and chemical shift reported as ppm downfield
3
2
15
ACS Paragon Plus Environment

Organic Process Research & Development
Page 16 of 25
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
to TMS. HRMS of the representative compounds were recorded using Thermofischer scientific
Q-Exactive plus Biopharma-High resolution Orbitrap, by the direct infusion method. The
isothermal study was carried on RC1e with the AP01-0.5-RTC-3w reactor, PTFE cover AP01-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0
.5, pitch blade stirrer 3-down. DSC measurements were performed with Mettler Toledo DSC 1
module, about 4mg of sample or solution 0.1 g/mL (unless stated) was taken in a 40µl high-
pressure gold-plated crucible and measured with dynamic heating run from 25 °C to 400 °C. The
nth order kinetic software is used to calculate activation energy and TMR.
Cautionary Note: Reactions and subsequent operations involving peracids should be performed
behind safety shield on small scale. For relatively fast reactions, the rate of addition of oxidant
should be controlled. The excess peroxide should be quenched with peroxide scavenger, before
distillation.
Table 4. N-oxide formation of substituted pyridine and the N-heterocyclic substrate.
R2
R2
R1
R1
1
b-11b
N
1
.m-CPBA, 10-15 °C; 30-35 °C
N
1a-11a
2.Na SO , 30-35 °C
2
3
O
R2
R2
3.NH3(g), 10-15 °C
R3
R1
R3
R1
12b-14b
N
N
12a-14a
O
Purity(%)b MP/BPd
Entry Substrate
Substitution
N-oxides Yield
c
(%)
°C
R1
R2
R3
-
1
2
1a
2a
H
H
1b
2b
98
99.6
99.5
65-66
43-45
2-CH3
H
-
98.5
16
ACS Paragon Plus Environment

Page 17 of 25
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
3
4
5
6
7
8
9
3a
4a
3- CH3
4-CH3
H
-
3b
4b
98.4
98.7
98.9
98.2
98.3
98.4
98.6
98.5
98.6
98.6
98.6
98.2
99.4
99.8
99.7
99.9
99.0
99.4
99.5
99.8
99.8
99.5
99.8
99.8
38-39
H
-
183-185
5a
2-CH3
3- CH3
-
5b
162-163d
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
108-110d
6a
2-CH3
6- CH3
-
6b
7a
3-CH3
5- CH3
-
7b
102-104
95-97
8a
2-C H CH
H
H
H
H
H
H
H
-
8b
6
5
2
9a
4-C H CH
-
9b
92-94
6
5
2
1
0
1
10a
11a
12a
13a
14a
4-O NC H CH
2
-
-
10b
11b
12b
13b
14b
153-155
295-298
54-55
2
6
4
1
2-pyridyl
12
H
2-CH3
H
H
1
1
3
4
H
68-69
8-OH
136-138
aExperimental condition: substrate (200.0 g, 2.53 mol to 1.86 mol, 1.0 equiv.), 75% m-CPBA
610.0 g to 450.0 g, 3.53 mol to 2.60 mol, 1.4 equiv.), Na SO (2g, 0.01 mol), isopropyl acetate (10
(
2
3
b
c
d
vol). Purity by GC. Isolated yield. Boiling point.
General procedure for 200g scale.
In a 3L, 4 neck round bottomed flask arranged with an overhead stirrer and outlet connected with
a trap containing 5% aq. oxalic acid, charged with pyridine (200.0 g, 2.52 mol) and isopropyl
acetate (2.0 ltr, 10 vol.) under stirring at 125 RPM. The reaction mixture was cooled to 10-15 °C
followed the addition of m-CPBA (75% w/w) (610 g, 3.53 mol, 1.40 equiv.) in 10 equal portions
over a period of 45-50 minutes and stirred further for 1h at 10-15 °C. The reaction was further
stirred at 30-35 °C for 4h. The reaction was monitored by GC. After completion of the reaction,
17
ACS Paragon Plus Environment

Organic Process Research & Development
Page 18 of 25
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
added solid sodium sulfite (2.0 g, 0.01 mol) to the reaction mixture and stir for 15 minutes. The
peroxide content was determined by MN-Quantofix peroxide strip. The reaction mixture was
cooled to 10-15 °C and anhydrous ammonia gas was sparged from the commercially available
cylinder, at the rate of 180-200 mL/min till the pH was raised to 8-9 excess ammonia escaping
was trapped in 5% aq. oxalic acid. The resultant slurry was filtered through Celite bed and
washed with isopropyl acetate 2 x 200 mL. The filtrate was transferred to the rotary evaporator
and the product was isolated by evaporation of solvent with 90% solvent recovery at 20 mm of
Hg and temperature not exceeding 50 °C, which resulted in the viscous oily product which
eventually crystallized on standing to furnish 235.0 g pyridine N-oxide (98% yield, 99.6%
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
purity). The purity of the product was determined by G.C Melting point 65-66 °C; H NMR
(
CDCl , 400MHz) δ 8.13 (dd, J = 5.4, 2.8 Hz, 2H), 7.21 (dd, J= 8.8, 6.4 Hz, 3H); FTIR (neat)
3
3
361, 3108, 1733, 1716, 1653, 1605, 1558, 1540, 1506, 1460, 1223, 1171, 1070, 1015, 914, 832,
-1
+
765, 672 cm ; HRMS elemental calculated for C H NO (MH ):95.0371; found: 95.0371.
5
5
RC 1 reaction procedure:
The experiment was performed in an isothermal calorimetry in RC1e. Initially, isopropyl acetate
350.0 mL, 17.5Vol) was added followed by pyridine (20.0 g, 0.252 mol) under stirring at 300
(
RPM. The homogeneous solution was cooled to 10 °C and m-CPBA (61.0 g, 0.353 mol, 1.40
equiv.) was added in 10 equal portions and heat of reaction was recorded. Each portion of m-
CPBA required approximately 2 mins for addition and we followed a trend of 5 min waiting after
the addition of each portion. The reaction mixture was maintained at 10 °C for 90 min. The
temperature of the reaction mixture was raised to 30 °C and was maintained for 1h. The excess
peroxides were quenched by adding sodium sulfite (0.2 g, 0.001mol) and heat of peroxide
quenching was recorded. The heat of peroxide quenching was negligible. The reaction mixture
18
ACS Paragon Plus Environment

Page 19 of 25
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
was cooled to 10 °C and ammonia gas was sparged at the rate of 180-200 mL/min. During
sparging at this rate, a rapid exotherm was recorded and the sparging was stopped to stabilize the
reaction mixture temperature at 10 °C. The sparging of ammonia gas was continued at a low
flow rate of 100-110 mL/min till the pH of the reaction mixture raised to pH 8-9 excess ammonia
escaping was trapped in 5% aq. oxalic acid. The slurry was filtered through Celite bed and
washed with isopropyl acetate 2 x 20 mL. The filtrate was transferred to the rotary evaporator
and the product was isolated by evaporation of solvent which resulted in the viscous oily product
which eventually crystallized on standing to furnish 23.3 g pyridine N-oxide (97% yield, 99.4%
purity by GC). Melting point 65-66 °C
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Kilo Scale Procedure:
In a 50L glass reactor with Teflon blade stirrer equipped in circulation bath with an external
chiller of 14-16 L/min thermal fluid flow rate, was charged isopropyl acetate (43.7 L 17.5 Vol)
followed by pyridine (2.5 kg, 31.64 mol) under stirring at 150 RPM. The reaction mixture was
cooled to 10-15 °C. Maintaining the temperature 10-15 °C m-CPBA (75% w/w) (7.62 kg, 44.15
mol, 1.40 equiv.) was added in 10 equal portions. Each portion of m-CPBA was added in 15
mins and was aged for further 10 min before next addition. After complete additions, the reaction
mass was maintained for further for 1h at 10-15 °C. The temperature of the reaction mixture was
raised to 30-35 °C and was maintained for further 4h. The reaction was monitored by GC. After
completion of the reaction, solid sodium sulfite (25.0 g, 0.19 mol) to the reaction mixture and stir
for 15 minutes. The peroxide content was determined by MN-Quantofix peroxide strip. The
peroxide test was negative. The reaction mixture was cooled to 10-15 °C and anhydrous
ammonia gas was sparged from the commercially available cylinder, at the rate of 100-110
mL/min for 1h, then the rate was increased to 150-180 mL/min for further 1h and 180-200
19
ACS Paragon Plus Environment

Organic Process Research & Development
Page 20 of 25
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
mL/min for 2h maintaining the temperature of reaction mass at between 10-15 °C to achieve the
pH of the reaction mass to pH 8-9. The excess ammonia was scrubbed using common scrubber
facility. The resultant slurry was filtered through Celite bed on S.S 316L Nutsche filter and the
cake was washed with isopropyl acetate 2 x 2.0 L. The filtrate was transferred to another 50L
glass reactor and the solvent was distilled by maintaining the thermal fluid bath temperature at
40-45 °C under vacuum (20 mm of Hg). After complete distillation of solvent, the residue was
degassed for 15 mins to ensure complete removal of solvent traces. The viscous oily product was
unloaded hot in HDPE container which eventually crystallized on standing to furnish 2.92 kg
pyridine N-oxide (97% yield, 99.4% purity). The G.C graph of kilo scale batch was concordant
with the standard pyridine N-oxide. (refer supplementary information). Melting point 65-66 °C.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Conclusions
An improved, safe and scalable preparation and isolation process for N-oxides of
(substituted)pyridines and quinolines with 98-99% yield with purity in the range of 98-99%
using m-CPBA-NH3(g) system was developed. The safety of the reaction at conversion as well as
isolation steps is substantiated by calorimetric data of reaction, isolated product. The proposed
protocol is not only economic but also eco-friendly due to efficient recovery and reusability of
the solvent as well as reagent precursor m-chlorobenzoic acid. The process flow is simplified
with minimized utility, waste yielding high purity products are the key features of this protocol
for scale-up which meets the industrial requirement of safety, cost-effectiveness. The improved
heat capacity due to solvent: reactant ratio of 17.5, controlled addition of m-CPBA and ammonia,
scavenging excess m-CPBA and cautious solvent recovery make the protocol to qualify most of
the safety criteria. Hence, it was feasible for us to demonstrate the safe operation at scale as high
as 2.5 kg batch.
20
ACS Paragon Plus Environment

Page 21 of 25
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
ASSOCIATED CONTENT
Supporting Information
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Supporting Information about spectral data and calorimetric analysis is available free of charge on
the ACS Publications website
AUTHOR INFORMATION
*
Corresponding author. Address: Department of Pharmaceutical Sciences and Technology,
Institute of Chemical Technology, Matunga, Mumbai - 400019, India. Tel.: 91-22-33612212,
Fax: 91-22-33611020
E-mail address: gu.chaturbhuj@gmail.com
†Indian Patent Provisional No: TEMP/E-1/29261/2018-MUM
ACKNOWLEDGMENTS
Authors are thankful to Loba Chemie Pvt. Ltd. for supporting this work and Mr. Parag
Chaudhary for preparing the DSC samples, Ms. Aprajita Singh for performing calorimetric
experiments on RC 1. Also, grateful to Mr. Vijay Bhujle and Mr. Ganesh Kumar Janardhan,
GVS Cibatech Pvt. Ltd for providing insight for interpretation thermal analysis.
REFERENCES
(1)
Wardman, P.; Priyadarsini, K. I.; Dennis, M. F.; Everett, S. A.; Naylor, M. A.; Patel, K.
B.; Stratford, I. J.; Stratford, M. R.; Tracy, M. Chemical properties which control
selectivity and efficacy of aromatic N-oxide bioreductive drugs. Br. J. Cancer. Suppl.
21
ACS Paragon Plus Environment

Organic Process Research & Development
Page 22 of 25
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
996, 27, 70–74.
(
(
(
2)
3)
4)
Chandler, C. J.; Segel, I. H. Mechanism of the antimicrobial action of pyrithione: effects
on membrane transport, ATP levels, and protein synthesis. Antimicrob. Agent Chemother.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
978, 14, 60–68.
Balzarini, J.; Stevens, M.; De Clercq, E.; Schols, D.; Pannecouque, C. Pyridine N-oxide
derivatives: unusual anti-HIV compounds with multiple mechanisms of antiviral action. J.
Antimicrob. Chemother. 2005, 55, 135–138.
Ghattass, K.; El-Sitt, S.; Zibara, K.; Rayes, S.; Haddadin, M. J.; El-Sabban, M.; Gali-
Muhtasib, H. The quinoxaline di-N-oxide DCQ blocks breast cancer metastasis in vitro
and in vivo by targeting the hypoxia inducible factor-1 pathway. Mol. Cancer 2014, 13,
1
2.
(5)
(6)
(7)
Sainz, Y.; Elena Montoya, M.; Javier Martínez-Crespo, F.; Ortega, M.; López de Ceráin,
A.; Monge. New quinoxaline 1,4-di-N-oxides for treatment of tuberculosis.
Arzneimittelforschung, 1999, 49, 55-59.
Vicente, E.; Villar, R.; Perez-Silanes, S.; Aldana, I.; Monge, R. C. G. Quinoxaline 1,4-di-
N-oxide and the potential for treating tuberculosis. Infect. Disord. Drug Targets. 2011, 11,
1
96–204.
Mannava, C.; Maddileti, D.; Khandavilli, U. B. R.; Swapna, B. Blonanserin N-Oxide
lowers glucose levels in animal models. J. Pharm. Drug. Dev. 2017, 4, 1-8.
(8)
Pingili, R. R.; Vurimidi, H.; Lilakar, J.; Madhusudhan, G. R.; Jonnalagadda, V. An
22
ACS Paragon Plus Environment

Page 23 of 25
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
improved process for the production of rabeprazole sodium substantially free from the
impurities. Org. Process Res. Dev. 2012, 23, 1021–1032.
(9)
Ahn, K. H.; Hakwon, K.; Jeong, R. K.; Tae, S. K. A New Synthetic Process of
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Lansoprazole. Bull. Korean Chem. Soc. 2002, 23, 626–628.
(
(
(
(
10) Ochiai, E. Recent Japanese work on the chemistry of pyridine 1-oxide and related
compounds. J. Org. Chem. 1953, 18, 534–551
11) Nagano, H.; Nawata, Y.; Hamana, M. The Mechanism of the reaction of nicotinic acid 1-
oxide with acetic anhydride. Chem. Pharm. Bull. 1987, 35, 4068–4077.
12) Grierson, D. The Polonovski reaction. Org. React.; John Wiley & Sons, Inc. 2004, 39, 85-
295.
13) Cave, A.; Kanfan, C.; Potier, P.; Le Men, J. Modification de la reaction de polonovsky.
Tetrahedron Lett. 1967, 23, 4681–4689.
(14) Mosher, H. S.; Turner, L. Pyridine N-oxide. Org. Synth. 1953, 33, 79.
(
(
(
15) Meisenheimer, J. Über Pyridin-, Chinolin- und Isochinolin-N-oxyd. Ber. Dtsch. Chem.
Ges. B. 1926, 59, 1848–1853.
16) Bobranski, B.; Kochanska, L.; Kowalewska, A. Über die Einwirkung von Sulfurylchlorid
auf Pyridinoxyd. Ber. Dtsch. Chem. Ges. B. 1938, 71, 2385.
17) Epsztajn, J.; Bieniek, A.; Kowalska, J. A. Application of organolithium and related
reagents in synthesis. Part 9. Synthesis and metallation of 4-chloropicolin- and 2-
chloroisonicotinanilides. A useful method for preparation of 2,3,4-trisubstituted pyridines
23
ACS Paragon Plus Environment

Organic Process Research & Development
Page 24 of 25
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Tetrahedron 1991, 47, 1697–1706.
(
(
(
(
18) Thellend, A.; Battioni, P.; Sanderson, W.; Mansuy, D. Oxidation of N-heterocycles by
H O catalyzed by a Mn-Porphyrin: An easy access to N-oxides under mild conditions.
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Synthesis (Stuttg). 1997, 12, 1387–1388.
19) Copéret, C.; Adolfsson, H.; Tinh-Alfredo, V. K.; Yudin, A. K.; Sharpless, K. B. A Simple
and efficient method for the preparation of pyridine N-oxides. J. Org. Chem. 1998, 63,
1
740–1741.
20) Rudolph, J.; Reddy, K. L.; Chiang, J. P.; Sharpless, K. B. Highly efficient epoxidation of
olefins using aqueous H O and catalytic methyltrioxorhenium/pyridine:ꢀ pyridine-
2
2
mediated ligand acceleration. J. Am. Chem. Soc. 1997, 119, 6189–6190.
21) Copéret, C.; Adolfsson, H.; Chiang, J. P.; Yudin, A. K.; Sharpless, K. B. A simple and
efficient method for the preparation of pyridine N-oxides II. Tetrahedron Lett. 1998, 39,
761–764.
(
(
(
22) Brown, D. B.; Ironside, M. D.; Shaw, S. M. Safety Notables: Information from the
literature. Org. Process Res. Dev. 2016, 20, 575–582.
23) Islam, A. N.; Tofik, N. I.; Tofik, B. B.; Mamedali, M. A. Oxidation of pyridine bases by
hydrogen peroxide. J. Chem. Eng. 2011, 5, 82–88.
24) Kubota, A.; Takeuchi, H. An Unexpected Incident with m-CPBA. Org. Process Res. Dev.
2
004, 8, 1076–1078.
(25) Caron, S.; Dugger, R. W.; Ruggeri, S. G.; Ragan, J. A.; Ripin, D. H. Large-Scale
24
ACS Paragon Plus Environment

Page 25 of 25
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Oxidations in the Pharmaceutical Industry. Chem. Rev. 2006, 106, 2943–2989.
(
(
(
26) Zhang, X.; Anjun, Hu.; Pan, C.; Zhao, Q.; Wang, X.; Lu, J. Safer preparation of m-
CPBA/DMF Solution in Pilot Plant. Org. Process Res. Dev. 2013, 17, 1591–1596.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
27) Stoessel, F. Thermal Safety of Chemical Processes: Risk Assessment and Process Design;
Wiley, New York, 2008.
28) McDonald, N.; Steppel, R. N. m-Chloroperbenzoic acid. Org. Synth. 1970, 50, 15.
25
ACS Paragon Plus Environment