Stability of Salt 5. The thermal stability of dried solid 5
was measured in ARC experiments, which indicated an onset
temperature of 120–130 °C over two different experiments with
different thermal inertia factors. The exotherm is energetic with
fast release of energy and decomposition as demonstrated by a
sharp rise in pressure under complete containment. However,
in the new process the salt was generated at around 0 °C and
was dried at approximately 20 °C, permitting the standard >50
°C safety margin. Additionally, dried 5 was tested for sensitivity
to impact using a dropping weight protocol. The material was
found to be insensitive to impact at the maximum test height
of the apparatus over 10 repeated runs, indicating that the
material is safe for normal handling.
of nitric acid with sulfuric acid and charging of the mixed acid
to the batch were eliminated from the process. The sulfuric acid
charge was reduced by 60%, which in turn led to 30% reduction
of maximum operation volume (25 vs 36 L/kg 4) and 40%
reduction of total generated wastes (50 vs 83 kg/kg 4). More
importantly, ∼59% yield improvement over the two steps (from
58% to 92%) was achieved. Thermal hazard analysis of the
key intermediates and key operations has concluded that the
process is safe to run under the operation conditions. An
ongoing study has shown that this nitration protocol can be
applied to a variety of substrates, and the results will be reported
in a separate paper.
Experimental Section
Reaction Calorimetry and Thermal Stability of Addition
of Dichloromethane Solution of 5 to Concentrated Sulfuric
Acid. The addition and reaction were determined to be
exothermic, and reaction enthalpy was determined to be 243.5
kJ/mole of 5. On the basis of an experimental determination of
cp, the adiabatic temperature rise was estimated to be 61.3 °C.
The reaction mixture consisted of two liquid phases, and under
sufficient agitation the rate of heat evolution was found to be
addition controlled over ∼30 min of addition time. No
significant residual (post-addition completion) reaction enthalpy
was observed. Post reaction completion the reaction mixture
was tested for thermal stability. The data indicated an exotherm
onset of 98.7 °C and a time to maximum rate from initiation
of approximately 200 min. Additionally there was a rapid
pressure buildup (under complete containment), indicating
exothermic decomposition. The normal process temperature was
0 °C. Therefore, if all of the dichloromethane solution of 5 was
to be charged instantly, the batch temperature could spike to
61.3 °C, which is less than the standard 50 °C margin from the
onset temperature. However, because of the absence of delayed
reaction exotherms and the fact that the rate of heat evolution
is substantially addition-controlled, the process can be run safely.
Drying of 4. Thermal stability of 4 was tested. A self heat
exotherm was detected with an onset temperature of 165 °C
and a predicted adiabatic temperature rise of >430 °C was
observed. The highest exposed temperature in the process for
4 was 45 °C (drying temperature). Therefore, there is a sufficient
safety margin for safe drying of the step product.
4-(4-Methoxyhenyl)morpholine, Nitric Acid Salt (5). A
1-L, 4-neck round bottom flask, equipped with a mechanical
stirrer and a nitrogen inlet, was charged with 20 g (0.162 mol)
of p-anisidine, 48 g (0.336 mol) of 2-chloroethyl ether, 1.04 g
(0.003 mol) of tetrabutylammonium bromide, and 77 g (0.8
mol) of 42% sodium hydroxide solution. The mixture was
refluxed at around 110 °C for about 8 h. After completion of
the reaction was confirmed, the mixture was cooled to 20 °C
and extracted with 50 mL of TBME and 50 mL of ethyl acetate,
respectively. The combined organic solution was washed with
80 mL of water. The organic solution was cooled to 0 ( 5 °C,
and to it was slowly added 14.6 g (0.162 mol) 70% HNO3. A
heavy precipitation was formed at the late stage of the addition.
After the addition the batch was aged for at least 1h. The solid
was filtered, washed with 40 mL of TBME, and dried under
vacuum at 45 °C overnight to give 40.2 g (97%) 5 as a tan
solid.
4-(4-Methoxy-3-nitrophenyl)morpholine (4). A 250-mL,
4-neck round bottom flask, equipped with a mechanical stirrer
and a nitrogen inlet, was charged with 80 g (0.815 mol) of 95%
sulfuric acid. The acid was cooled to ∼0 °C. A solution of 20 g
(0.078 mol) of 5 in 125 mL of dichloromethane was slowly
added to the acid while the batch temperature was maintained
at 0 ( 5 °C. After the addition the mixture was stirred for 30
min. The agitation was stopped, and the bottom acid layer was
separated. The acid solution was slowly added to 200 mL of
water while maintaining the temperature at <10 °C. To this
diluted acid solution was then slowly added 190 mL of 28%
NH4OH solution while the temperature was maintained at <10
°C. At the end of the addition the pH of the mixture should be
higher than 10. The batch was aged at 5 ( 5 °C for 1 h. The
solid was filtered, washed with 50 mL of water, and dried under
vacuum at 45 °C overnight to give 17.5 g (94% yield) of 4 as
an orange solid.
Conclusion
To the best of our knowledge, this is the first example of
carrying out nitration using isolated nitric acid salt of a substrate.
This approach provides an ease and reliable way to obtain an
exact 1:1 molar ratio of substrate and nitric acid, which may
be otherwise difficult to achieve especially on a manufacturing
scale using fixed equipment. In our case, this method has been
proven to be the most effective way to prevent under-/over-
nitration and thus contributed to the substantially improved
robustness of the process. Furthermore, the incorporation of the
method added other benefits to the whole process. For instance,
direct precipitation of 5 from the step 1 extract resulted in the
elimination of solvent exchange and crystallization operations
used for the isolation of free base 3 in step 1. The replacement
of charging solid 3 to sulfuric acid with addition of a
dichloromethane solution of 5 to sulfuric acid made the process
safer and more operation friendly. The operations of premixing
Acknowledgment
We thank Dr. Geng-Xian Zhao, Ms. Joni Bishop, and Ms.
Eileen Zhao for their analytical supports.
Supporting Information Available
Process hazard analysis data. This information is available
Received for review March 28, 2007.
OP700074K
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Vol. 11, No. 5, 2007 / Organic Process Research & Development