to volume with acetonitrile. Nitroacid and impurity peaks
are reported by reference to the corresponding nitroacid and
impurity standards. The in-process test to check for complete
reaction was similar but used an isocratic method run over
25 min with eluent composed of acetonitrile (500 mL), water
(500 mL), and glacial acetic acid (2 mL), all other parameters
being the same as those described above.
about one-third has been added, which results in a thick slurry
initially. The reaction mixture is cooled to 35 °C over ∼40
min and the product isolated by filtration immediately. The
reactor is rinsed with water (186 mL) and used to slurry wash
the product. The product cake is then sequentially washed
by displacement with water (116 mL) and acetone (136 mL),
slurry is washed with acetone (157 mL), displacement is
washed with acetone twice (116 mL and 128 mL) and dried
in vacuo at 60 °C (in the lab; in the plant, the product is
dried by hot nitrogen at 80 °C on a pressure filter). The
product nitroacid is a bright-yellow solid obtained in typically
81-85% yield (uncorrected for nitroester input) with strength
close to 100%.
Variations to Standard Nitroacid Process. In the
variations below where no values are given, assume the
standard process parameters have been used.
Acid Molarity. Batch 103 used with pre-acidification water
charge adjusted as follows: concentrated (11.6 M), no change
(147 mL); 8 M, 139 mL; 6 M, 131 mL; 5 M, 124 mL; 3 M,
96 mL; 2 M, 60 mL; 1 M, 0 mL.
Nitroester Batch. Nitroester batches used with C2C3-
diester levels as follows: 94×, 0.99; 102×, 0.49; 103, 0.82;
105, 0.58; 108, 1.04% w/w. Concentrated and 2 M HCl used
with appropriate water charges, isolated at pH 2.
Acid Addition Time. Batch 108 used with 60 mL water
charge and 2 M HCl; acid addition times as shown in Figure
6.
Agitation Rate. Batch 108 used with 60 mL water charge
and 2 M HCl added over 120 min; agitation rates at 150,
200, and 340 rpm in standard laboratory equipment (Figure
7).
Hold at 50 °C before Acidification. Batch 103 used with
60 mL water charge and 2 M HCl added over 50-55 min;
hold periods of 0, 24, and 96 h before acidification.
Acid Addition Temperature. Batch 108 used with 60 mL
water charge and 2 M HCl added over 180 min; acid addition
temperatures of 42, 52, and 60 °C.
Hold at 35 °C before Isolation. Batch 108 used with 60
mL water charge and 2 M HCl added over 75-80 min. A
double-sized batch was prepared, acidified, and split in two,
and the first half was isolated immediately at 35 °C. The
second half was held at 35 °C from which 10-mL aliquots
of slurry were taken at 16 and 44 h and individually worked
up with solvent washes adjusted for scale accordingly. The
remainder of the batch was isolated after 68 h and isolated
with appropriately adjusted solvent washes (Figure 8).
Isolation Temperature. Batch 108 used with 60 mL water
charge and 2 M HCl; isolation temperatures of 28, 35, and
42 °C.
Determination of Nitroacid pKa. A pure sample of
nitroacid was prepared using the standard procedure below
from doubly recrystallised nitroester, so that the UV absor-
bance of the residual trace impurities present was minimal
(the maximum residual impurity was ∼0.05% w/w). A
number of wavelengths were assessed on a dilute solution
(0.1 mg/mL) of nitroacid in 50/50 THF/water. A maximum
difference of 0.6 absorbance units was found at 304 nm
between the spectra for the protonated (pH 1.6) and dissoci-
ated (pH 8.4) forms. A very dilute solution of nitroacid (100
mg) in 50/50 THF/water (1000 mL) was then acidified from
pH 8.0 to pH 4.0 by the addition of 0.1 M HCl, and UV
spectra were taken at ∼0.05 pH units intervals. The change
in absorption between the dissociated and protonated forms
of nitroacid could be determined from the UV spectra as
shown in Figure 1, from which an approximate figure for
the pKa of nitroacid could be determined as ∼6.2. Within
(0.6 pH units of the approximate pKa value, the following
equation can be used:
(A - AI)
pKa ) pH + log
(AM - A)
where AI ) absorbance of the fully dissociated (i.e. ionized)
species, AM ) absorbance of the fully protonated (i.e.
molecular) species, A ) absorbance at a given pH.
Using the equation the calculated value of the pKa was
determined as 6.24, from which a working value of 6.2 was
taken.
Standard Preparation of Nitroacid using Concentrated
HCl Process. Nitroester (38.7 g at assumed 100% strength,
114 mmol) was dissolved in THF (120 mL) by heating to
35 °C with stirring for 30 min to ensure complete solution,
before cooling back to 20-25 °C. Water (39 mL) was added,
followed by NaOH (27.0 g, 18.0 mL at 47% strength w/w
(100° Tw)) in one portion which resulted in an 8 K exotherm
on this scale. The reaction mixture was cooled back to 20-
25 °C, and methyl iodide (19.6 g, 8.6 mL, 138 mmol) was
added in one portion, followed by a line wash of THF (2
mL). The reaction mixture was stirred at 20-25 °C for 2 h,
after which time the methylation reaction is ∼70% complete.
Additional THF (14 mL) and water (19 mL) are added, and
the reaction mixture is heated to reflux at 65 °C over ∼1 h
(NB: The additional THF and water charges are to mimic
vessel/lines washes that occur in the plant when the batch is
transferred to a second plant vessel at this point). The
methylation reaction is completed during the heat up. The
mixture is held at reflux for 3 h, then cooled back to 50 °C.
Water (147 mL) is added, keeping the temperature in the
range 50-55 °C. Concentrated HCl (up to 21.7 g, 18. 4 mL
of 36% strength w/w (36° Tw)) is added smoothly over 1 h
until pH 1-2 is achieved. A yellow precipitate forms after
Pre-acidification Water Charge (separate from acid
molarity investigation). Batch 108 used with 2 M HCl; water
charges as shown in Figure 9.
Preparation of DMAP Salt. Nitroacid (29.5 g at assumed
100% strength, 86.8 mmol) and DMF (0.75 mL, 9.7 mmol)
were stirred in dichloromethane (203 mL) and heated to
reflux (41 °C). Thionyl chloride (10.9 g, 6.7 mL, 91.6 mmol)
was added over 20 min followed by a line wash of
dichloromethane (4 mL) and the heating continued at reflux
812
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Vol. 8, No. 5, 2004 / Organic Process Research & Development