Development of manufacturing processes for a new family of 2,6-dihaloaryl 1,2,4-triazole insecticides

Article abstract of DOI:10.1021/op9001577

Details are presented on the process development work for the new 2,6-dihaloaryl-1,2,4-triazole insecticide 1, and the development of a one-pot process toward a potential commercial manufacturing process.

Full text of DOI:10.1021/op9001577

Organic Process Research & Development 2009, 13, 1125–1129
Development of Manufacturing Processes for a New Family of 2,6-Dihaloaryl
1,2,4-Triazole Insecticides
John W. Hull, Jr.,* Duane R. Romer,* Timothy J. Adaway, and David E. Podhorez
The Dow Chemical Company, Engineering and Process Sciences, 1710 Building, Midland, Michigan 48674, U.S.A.
Scheme 1. Routes to 2,6-dihaloaryl-1,2,4-triazoles 1 and 2a
Abstract:
Details are presented on the process development work for the
new 2,6-dihaloaryl-1,2,4-triazole insecticide 1, and the development
of a one-pot process toward a potential commercial manufacturing
process.
Introduction
Effective insecticides will continue to be a critical need for
world agricultural markets, as it has been estimated that up to
15% of annual global food crops are lost to insects.1 The search
for safe and effective insecticides that exhibit low biopersistence
and low mammalian and aquatic toxicity continues to be a
significant agricultural challenge for the 21st century. The two
major trends of an ever-growing world population together with
the need for environmentally sustainable agricultural food
products would sometimes appear to be at odds with one
another. Dow AgroSciences has been investigating a new family
of 2,6-dihaloaryl 1,2,4-triazole insecticides2 featuring targeted
insecticidal activity coupled with low mammalian toxicity.
We have previously reported laboratory results detailing our
work on developing feasible synthetic routes for the thiophene
ring of this class of compounds.3 Synthetic methodologies were
also developed for construction of the 2,3,4-triazole ring system,
along with coupling strategies for these two heterocycles to
afford the target 2,6-dihalo insecticides. This route, shown in
Scheme 1, gave the desired product, 2,3,4-triazole 1, in four to
five steps, in good yield and high purity.
a Reaction conditions: (a) H2S, Et3N, 1,4-dioxane, <0 °C. (b) (MeO)2SO2,
1,4-dioxane, 80°C; or CH3Br, 1,4-dioxane, 25-80 °C. (c) 6, 3-picoline, 1,4-
dioxane. (d) CH3NHNH2, 1,4-dioxane, 50% NaOH, 40-80 °C. (e) 3-Picoline,
8, 23°C. (f) CH3NHNH2, 1,4-dioxane, 80 °C. (g) HOAc, NaOAc, Br2, 80 °C;
then Zn powder, 78 °C.
Although this route proved suitable as a laboratory process
to provide initial quantities of material for biological screening,
when kilogram quantities of 1 were required for field trials, the
shortcomings of this route became unmanageable. For example,
this laboratory process requires the solids isolation of three
intermediates, along with the use of three different process
solvents. Clearly, for the production of multikilogram quantities,
as well as a potential manufacturing route, a more simplified
pilot plant process having fewer unit operations was desirable
that could lead ultimately to a low cost commercial scale
process.
One of the recent trends in Dow Process R&D is to develop
manufacturing routes which minimize the number of isolations
and seeks to find common solvents to simplify recycle streams.
In this work, we describe our efforts to develop a one-pot and
common solvent process for the production of 1.
Results and Discussion
The initial laboratory route for the preparation of 1 and 2 is
shown in Scheme 1. 2-Chloro-6-fluorobenzonitrile 3 was treated
with H2S in Et3N as the solvent, followed by methylation to
give the thioamidate salt 5. This is then coupled to a thiophene
carboxylic acid chloride 6 or 8, giving the thioamidate esters 7
and 9. Finally, cyclization with methylhydrazine leads to the
target compounds 1 and 2. Alternatively, a bromination/
reductive debromination of 2 also gives 1.
* Authors for correspondence. E-mail: jwhull@dow.com; drromer2@
dow.com.
(1) McMurry, J. Organic Chemistry, 4th ed.; New York: Brooks/Cole
Publishing Co; 1996, p 759.
(2) Cudworth, D. P.; Hegde, V. B.; Yap, M. C. H.; Guenthenspberger, K. A.;
Hamilton, C. T.; Pechacek, J. T.; Johnson, P. L.; Bis, S. J.; Tisdell,
F. E.; Dripps, J. E.; Bruce, T. J.; Dintenfass, L. P.; Gifford, J. M.; Karr,
L. L.; Kempe, M. K.; McCormick, D’L. C.; Schoonover, J. R., Jr. J.
Agric. Food Chem. 2007, 55 (18), 7517.
For the development of a one-pot process to the triazoles 1
or 24 a common solvent was preferred. All of the steps in the
(3) Hull, J. W.; Romer, D. R.; Podhorez, D. E.; Ash, M. L.; Brady, C. H.
Beilstein Journal of Organic Chemistry; Clayden, J., Ed.; Beilstein
Institut: Frankfurt, Germany, 2007; Vol. 3, p 23.
(4) Podhorez, D. E.; Hull, J. W., Jr.; Brady, C. H. U.S. Patent 6,096,898,
2000; CAN 133:135314.
10.1021/op9001577 CCC: $40.75  2009 American Chemical Society
Published on Web 11/02/2009
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Scheme 2. Thiol and thioether impurity formed in the
To circumvent this problem, the thioamidation reaction was
investigated using catalytic levels of Et3N, and this was found
to be successful using 5-20 mol % of Et3N based on starting
material 3. With this approach, Et3N remained in the reaction
mixture and was deactivated in the next step by methylation to
the quaternary ammonium salt, now present at lower catalytic
levels. This deactivation of Et3N is critical, as it prevents
reversion of 4 back to 3 upon application of heat and removal
of residual H2S. Also, excess residual H2S was found not to be
detrimental to the methylation reaction and could be removed
from the reaction mixture after that step.
thioamidation step
process were compatible with 1,4-dioxane, and this solvent was
particularly convenient for isolation of the final products. By
simply adding an excess of water to the reactor, a separation
of the technical-grade product as an oil occurred. Therefore,
we focused our efforts to develop a one-pot process for 1 using
1,4-dixoane as the common solvent for all reaction steps.
The key starting material, 2-chloro-6-fluorobenzonitrile 3,
was obtained from a 2,6-difluorobenzonitrile production plant
as a 92 GC area % pure compound. Initial preparation of
benzthioamide 4 from 3 was carried by the addition of H2S
gas to 3 in pyridine in the presence of Et3N,5,6 with the exception
that the reaction temperature was lowered to <0 °C to minimize
the formation of an undesired thiol byproduct 10 (Scheme 2).
This thiol byproduct arises from the displacement of fluoride
from 3 by H2S, rather than attack on the cyano functionality,
giving thiol 10. The thiol can then undergo further coupling
reactions with 3 in the presence of excess base to form higher
thioethers 11. Early laboratory experiments demonstrated that,
by carrying out the thioamidation reaction at -10 to -20 °C,
the coupling side reactions to form thioethers were minimized,
and cleaner thioamidate 4 was isolated as a white microcrys-
talline solid by quenching the reaction mixture with water in
which the thiol byproduct 10 was soluble.
Success in developing a one-pot process for a series of
reaction steps hinges on the ability to remove certain reagents
from the reaction mixture without isolating the key reaction
intermediates. This can be accomplished in various ways by
using aqueous wash steps, distillation operations, filtrations, and
such. The first goal in developing a one-pot process for 1 or 2
was to eliminate the isolation of benzthioamide intermediate
4, which would avoid the production of a large aqueous waste
stream and a solids isolation step.
Fortunately, initial tests showed that using 1,4-dioxane
solvent in place of pyridine in the thioamidation step led to
high yields of 4 in solution, with minimal formation of the
undesired byproduct 11. However, in order to take advantage
of this ability to use a common solvent across multiple reaction
steps and eliminate the isolation of 4, Et3N base used during
this thioamidation step must be removed from the reaction
mixture to prevent its methylation to MeEt3N+Br- by MeBr in
the subsequent reaction step. This quaternization reaction, while
not directly interfering with the desired product chemistry,
would consume an excess of methylating agent and produce a
relatively large amount of quaternary ammonium salt in the
waste stream. Initial attempts to remove excess Et3N from the
post thioamidation reaction mixture by distillation showed that
this reaction is easily reversible. Thus, as excess H2S was
removed and moderate heat applied, 4 reverted back to the
starting material 3 in the presence of Et3N.
In practice, it was found that the most convenient approach
to carrying out the thioamidation reaction was with a moderate
H2S pressure of 30 psig in a pressure vessel and heating at 60
°C in 1,4-dioxane solvent and 20 mol % Et3N. This approach
can also be readily applied to a commercial manufacturing scale.
However, for laboratory development efforts, we used the
following process under atmospheric conditions that could
readily be adapted to operating under mild pressure ranges in
a pilot-plant or commercial-scale process. The thioamidation
reaction could be effectively carried out at atmospheric pressure
in a standard jacketed glass reaction vessel by sparging H2S
gas into a 60 °C solution of 3 and catalytic Et3N in 1,4-dioxane.
A dry ice trap was applied to the reactor to condense liquid
H2S, and 1.5-1.7 mol equiv of H2S gas sparged into the 60 °C
solution as fast as the dry ice condenser allowed. In this manner
the thioamidation reaction was carried out to high conversion
within a 24 h period with >95 GC area % of 4 attainable.
Laboratory reactions had shown that methylation of 4 to give
the thioamidate salt 5 was most conveniently accomplished with
dimethylsulfate as the methylating agent. Using 1.3 mol equiv
of dimethylsulfate, a quantitative conversion of 4 to 5 was
achieved within 3 h at 75 °C. However dimethylsulfate is
considered too hazardous for scale-up to a commercial process.
Thus, the use of methyl bromide (MeBr) gas as the methylating
agent was investigated. A higher molar excess of MeBr of
1.5-2.0 equiv and slightly higher temperature (80 °C) was
required to attain high conversion of 4 to 5. The 20 mol % of
Et3N remaining from the previous step reacted with MeBr to
form the quaternary ammonium salt, and the excess H2S
prevented reversion of 4 back to 3. During the course of MeBr
addition, 5 (as the Br- salt) precipitated from solution. After
methylation, excess dissolved H2S gas was removed from the
reactor by a subsurface nitrogen sparge of the reaction mixture
to sweep residual dissolved H2S into a bleach scrubbing
solution.
The coupling step to attach thiophene acid chloride 6 or 8
to the imine nitrogen of 5 (Scheme 1), to give either the
thioimidate 7 or 9 required a pyridine base to promote the
reaction. As both H2S and MeBr will react with pyridine
necessitating additional quantities of the base, a thorough
sparging of the reaction mixture was required prior to the
acylation coupling step to remove these two materials. Triethy-
lamine (TEA), pyridine, and 3-picoline were investigated as
bases in this step. TEA led to lower yields in the subsequent
cyclization step with methylhydrazine. The other bases gave
good results for both the coupling and subsequent cyclization
steps, but 3-picoline was chosen on the basis of cost. At least
(5) Fairfull, A. E. S.; Lowe, J. L.; Peak, D. A. J. Chem. Soc. 1952, 742.
(6) Abbas, K. A.; Edward, J. T. Can. J. Chem. 1985, 63, 3075.
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Scheme 3. Thiophene bromination chemistry
two equivalents of 3-picoline are required, one to neutralize
the acid equivalent in the protonated 5 salt and one to neutralize
the HCl byproduct of the acylation. Laboratory results showed
that 2.3-2.7 mol equiv of base were found to be most effective
in terms of yield of the desired product and efficiency of the
reaction.
powder was used to quench the two extra equivalents of Br2.
This is an exothermic reaction (-95 kcal/mol)7 and was
controlled by the addition of zinc powder to the reactor in small
portions.
A total of 4 mol equiv of zinc were used to quench the excess
bromine and effect the debromination reaction to give 1. The
debromination reaction of 13 to give 1 was highly selective for
only removal of the ortho bromine, even with an excess of zinc
powder and extended heating at 80 °C; for example, the reaction
mixture can be stirred overnight at 80 °C without side reactions.
As a note of caution, the addition of excess zinc powder to
a solution of aqueous acetic acid leads to the evolution of H2
gas along with the production of zinc acetate salt. Thus,
precautions were taken against flammability and explosion
hazards. Knowledge of the explosion limits of hydrogen/
nitrogen mixtures is essential at this step to allow for sufficient
dilution of the reactor head space with a nitrogen purge stream
in order to remain outside the flammability window.
Each of the two routes to 1 had certain advantages over the
other. The availability of bromothiophene 6 allowed for the
assembly of 1 with the bromine prepositioned on the thiophene
ring. However, this route also requires a recrystallization step
to produce low-odor material, a critical aspect of product
integrity for a commercial process. Use of the thiophene
building-block 8 gives the 2,6-dihalo product 2, which requires
additional bromination/debromination steps to prepare 1. How-
ever, this route also gives low-odor material without a cleanup
step required. Also, certain processing challenges exist with the
bromination/debromination of 2 to 1, which requires the careful
addition of zinc powder in a highly exothermic reaction,
and the generation of hydrogen gas as a coproduct. Thus, due
to the general ease of operation and the availability of a process
to the bromothiophene building-block 6 as previously reported,3
the bromothiophene route using 6 was favored to advance. The
route to 1 via 6 and 7 was readily applied on a multikilogram
scale using 22-L glass reactors in a laboratory pilot-plant
operation. The challenge of odor present in technical-grade 1
obtained from this route was addressed with a single recrys-
tallization from 2-propanol, which also served to enhance the
chemical purity. Thus, a high-grade product was readily
obtained with this route as defined by low odor and high
chemical purity.
Small-scale laboratory studies had shown that the methyl-
hydrazine cyclization step to produce the 2,6-dihalo-aryl-1,2,4-
triazoles 1 or 2 could be carried out without isolation of the
thioimidates intermediates 7 or 9. The use of a strong base was
required, and 50% aqueous NaOH was the base of choice for
this step. Two molar equivalents of methylhydrazine was added
to the reaction mixture, followed by 50% aqueous NaOH, and
the reaction mixture was heated at 80 °C to effect conversion
to the triazole ring system. In this step, sodium methanethiolate
is produced as a stoichiometric byproduct. Thus, a slightly basic
pH was maintained to control the stench of methanethiol.
Isolation of 1 obtained via bromothiophene 6 was ac-
complished by dilution of the reaction mixture with water and
separation of crude 1 as an oil. The oil was readily separated
from the aqueous phase as the bottom phase and was then added
to aqueous ethanol with cooling to effect precipitation of 1 as
a tan solid with a purity of 95 wt %. The isolated yield of
technical-grade 1 was 69% based on 3 and 65% based on 6 as
starting materials. The final product 1 could be further purified
by recrystallization from warm 2-propanol to give a product
purity of 99 wt %, which also ameliorated the disagreeable thiol
odor.
The final step to 1 via thiophene 8 was carried out using a
bromination/debromination approach (Scheme 3). A benefit to
this process is bromine effectively oxidizes all residual thiols
remaining in 2, and odor-free 1 is obtained from the reaction.
Although the production of 2 was also compatible with the one-
pot process using 1,4-dioxane as the common solvent, the
bromination/debromination step was not, and therefore 2 must
be isolated prior to bromination.
The bromination of 2 requires an excess of Br2 to achieve
full conversion to the dibromide. The first bromination is rapid
and exothermic, presumably forming the initial R-bromo
intermediate 12. However, the second bromination, placing a
bromine atom on the deactivated 4-position of the thiophene
ring, required an additional 3 equiv of bromine and 6 h at 80
°C to produce 13.
Initially charging 4 equiv of Br2 in acetic acid allowed for
the rapid and clean conversion of 2 to 13 after 1 h at 80 °C. To
carry out a “one-pot” approach, water was added to the reactor
after the bromination step was complete, and an excess of zinc
(7) The NBS Tables of Chemical Thermodynamic Properties; J. Phys. Chem.
Ref. Data, Vol. 11, Suppl. 2, NSRDS, U.S. Government Printing Office:
Washington, DC, 1982.
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Summary and Conclusion
quickly detect the presence of any fugitiVe H2S emission from
the reactor and scrubber systems, H2S detector tape was
obtained from MDA Scientific (H2S Chemcassette LP part
number 711304) and used inside the hood and around the
reactor and scrubber glass joints and at the scrubber Vent. This
paper tape is capable of detecting Very low ppm leVels of H2S
that allowed for the quick repair of any leaking joints. In this
manner fugitiVe H2S gas emissions into the hood and atmo-
sphere were minimized.
One-Pot Process to 1 using Brominated Thiophene 6. Step
1. Thioamidation of 3. A 22 L jacketed glass reactor was fitted
with a dry ice condenser, and the condenser was vented to a
bleach reservoir containing 20 L of 12% bleach solution. Under
a N2 purge the vessel was charged with 1,4-dioxane (6000 mL),
Et3N (130 g, 180 mL, 1.3 mol), and 2-chloro-6-fluorobenzoni-
trile (3) (1000 g, 6.43 mol). While the stirring mixture became
homogeneous, the condenser was cooled with dry ice/2-
propanol. The jacketed vessel was heated to 60 °C, and
hydrogen sulfide gas (375 g, 11.0 mol) was introduced below
the surface of the stirring solution. Approximately 80% of the
H2S was added during an 8 h shift, with the remainder added
the following morning after holding the reactor temperature
overnight at 60 °C. The H2S addition rate was manually
regulated to control the bleach scrubber solution temperature
to >25 °C and the reflux rate. The reaction mixture was stirred
overnight at 60 °C and then sampled by HPLC to ensure
complete conversion to 2-chloro-6-fluorothiobenzamide 4 and
then cooled to 25 °C.
Step 2. Methylation of 4. The same vessel described above,
including the dry ice/2-propanol condenser, was used for the
methylation reaction. However, the bleach scrubber was vented
to a trap containing 1.5 L of perchloroethylene. A heat lamp
was used on the MeBr (bp 4 °C) lecture bottle to increase the
gas-flow rate. Aluminum foil was used to protect the reactor
from the light of the heating lamp. To the stirring, dark-brown
reaction solution of 4 at 25 °C was added MeBr gas (800-900
g, 8.4-9.5 mol) over 5 h. After a third of the MeBr had been
added, the vessel was heated to 80 °C for completion of the
MeBr gas addition. During the gas addition the reaction mixture
changed from a dark-brown solution to an orange solution and
then to a yellow slurry. The mixture was stirred at 80 °C for
6 h and then was analyzed by GC for >98% conversion of 4 to
methyl 2-chloro-6-fluorothiobenzimidate bromide salt (5). A
subsurface N2 purge was introduced to the mixture for 11 h,
while the dry ice condenser came to ambient temperature and
the reaction slurry was cooled to 40 °C. The N2 purge was
discontinued after no additional H2S was detected at the reactor
vent by detector paper.
A one-pot process has been developed as a preliminary
process to produce the new 1,2,4-triazole experimental insec-
ticide 1. This one-pot process has been used to prepare kilogram
quantities of the triazole compound. 1,4-Dioxane was found to
be an effective solvent for all reaction steps except the
bromination/debromination step for the conversion of 2 to 1,
thus requiring a single isolation. The process for 1 utilizing the
brominated thiophene intermediate 6 produced 1 containing
some odoriferous residual sulfur compounds, while the bromi-
nation/debromination route from 2 produced odor-free technical-
grade product. Thus, the bromothiophene route required a final
recrystallization step to obtain low-odor product. For the
bromothiophene one-pot process, a 69% isolated technical-grade
yield of 1 based on 3 and 65% based on 6 was obtained. The
purity of the technical-grade material was 96%. Final recrys-
tallization to obtain low-odor product gave an 86% recovery
as a first crop from 2-propanol, resulting in an overall isolated
yield of 56-59% of 1 with a final chemical purity of 99+%.
Experimental Section
Raw Materials. Kilogram quantities of 3-methyl-2-thiophen-
ecarbonyl chloride (6) and 2-chloro-6-fluorobenzonitrile (3)
were purchased from Lancaster Synthesis.8 Preparation of
3-methyl-thiophenecarbonyl chloride (6) and 4-bromo-3-methyl-
2-thiophenecarbonyl chloride (8) has been reported separately.3
Samples of 6 and 8 were also purchased in 5 kg research
quantities from Shasun Chemical and Drugs, Ltd. of India.9
ReVerse-phase HPLC Conditions: Zorbax Rx C8 column,
4.6 × 250 mm; UV detector at 220 nm; 60/40 CH3CN/H2O
with 0.07 wt. % H3PO4 at 1.0 mL/min flow rate; biphenyl as
internal standard for reaction samples, benzophenone as internal
standard for assay of 1. Retention times (min): 5, 3.4; 4, 3.9; 3,
5.6; 1; 9.2.
GC Conditions: DB-5 column, 15 m × 0.53 mm, 1.5 µm
film; FID detector, N2 carrier gas; oven heating 60 °C for 3
min, 15 °C/min to 250 °C for 5 min; biphenyl as internal
standard for reaction samples, benzophenone as internal standard
for assay of 1. Retention times (min): 3, 6.9; 6, 9.4; 4, 11.7; 7,
17.5; 1, 17.8.
Elemental analyses were performed by Galbraith Laboratories.
Technical-grade 3 was obtained from a Dow AgroSciences
production facility as a byproduct of another process that was
distilled to give a 92% pure material by GC area % and further
purified by recrystallization. Details of the purification of
2-chloro-6-fluorobenzonitrile 3 by batch recrystallization and
the isolation of reaction intermediates can be found in the
Supporting Information.
Handling H2S Gas. Caution! Hydrogen sulfide gas is
flammable and toxic and may be fatal with sufficient exposure.
It is an insidious poison in that the sense of smell can be fatigued
and lead to an inability to detect high concentrations. It should
be handled only by qualified personnel in a well-Ventilated fume
hood using a bleach/NaOH scrubber system to quench excess
amounts Venting from the reactor. In order to readily and
Step 3. Coupling of 5 with 4-bromo-3-methyl-2-thiophene-
carbonyl Chloride (6). The dry ice condenser on the 22 L reactor
from above was replaced with a water condenser. The reactor
jacket temperature was set to 20 °C, and 3-picoline (1359 g,
16.4 mol) was added over 20 min via peristaltic pump. During
the addition, the internal reaction temperature remained <50
°C. The initial yellow slurry became an orange solution after
stirring for 15 min after 3-picoline addition was completed. The
jacket temperature was set to 10 °C, and 6 (2720 g, 6.81 mol)
as a 60 wt % solution by volume in 1,4-dioxane was added to
(8) Lancaster Synthesis. Now a part of Alfa Aesar, a Johnson Matthey
company; www.alfa.com.
(9) Shasun Chemical and Drugs, Ltd. of India. www.shasun.com.
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the reactor over a 1 h period via peristaltic pump. The addition
rate of 6 was adjusted such that the internal reactor temperature
remained below 50 °C. After the addition was completed, the
mixture was stirred at 10 °C jacket temperature for an additional
2 h. Analysis of a reaction sample by GC indicated that
quantitative conversion of 5 to 7 had occurred.
∼1800 g of technical-grade 1 as a tan solid, with a purity of
95% by HPLC assay method (4.42 moles based on assay). This
technical-grade solid product exhibited a disagreeable odor.
Recrystallization of 1. A 2000 g sample of technical-grade
1 was dissolved into warm 2-propanol (7.2 L) at 75 °C. Cooling
the solution to 15 °C gave solid 1 which was collected on a
filter, rinsed with about 500 mL of fresh 2-propanol, and air-
dried in a glass tray to a constant weight over 24 h to give
1731 g of 1 (86.6% recovery), as a tan solid with only a faint
odor present, and an HPLC assay of >99% purity; mp 120-
121 °C.
Preparation of an Analytical Standard of 1. A 554 g sample
of recrystallized 1 from above was dissolved in CH2Cl2 and
passed through a short column of silica gel. The eluant was
stripped to dryness, recrystallized from warm 2-propanol (1270
g) as above, and air-dried to give 519 g (93.7% recovery) of 1
as a pale-yellow solid; mp 121-123 °C, 111 ppm water by
Karl Fischer titration, and an HPLC and GC area % purity of
>99%; 1H NMR (CDCl3): δ 7.4 (s, 1 H), 7.3 (m, 2 H), 7.1 (t,
1 H), 4.0 (s, 3 H), 2.3 (s, 3 H); 13C NMR δ 163.2, 159.8, 155.0,
149.4, 139.8, 135.6, 131.2, 125.6, 122.2, 120.0, 114.6, 114.3,
36.9, 15.4. Anal. Calcd for C14H10BrClFN3S C, 43.49; H, 2.61;
N, 10.87. Found: C, 43.44; H, 2.52; N, 10.77.
Step 4. Cyclization of 7 to 1. The 22 L jacketed vessel from
above was heated to 40 °C, and 98% methylhydrazine (440 g,
9.98 mol) was added to the reactor via peristaltic pump over
1 h. Immediately following the addition, 50% NaOH (1029 g,
12.9 mol) was introduced to the vessel at 43 °C over 1 h, or at
a sufficient rate so as to maintain the reaction temperature below
50 °C. After completion of the addition of NaOH, the reaction
mixture was stirred at 80 °C for 15 h. After this time a GC
analysis indicated >98 area % conversion of 7 to 1. The reaction
mixture was cooled to 50 °C and sparged with N2 for 1 h. Water
(10.6 L) was added via pump and the reactor temperature re-
established at 50 °C. The stirring was halted, and the phases
slowly separated over 2-3 h. The dark-brown bottom organic
phase along with a small emulsion layer was removed from
the reactor at 50 °C and placed in bottles.
Step 5. Crystallization/Isolation of 1. A 12 L jacketed vessel
was charged with 95% EtOH (2790 mL) and water (1200 mL).
The crude oil from step 4 above was added over 15 min to the
stirring EtOH/H2O solution. The vessel jacket was set to 20 °C
and stirred for 2 h. The solid product, 1, precipitated from the
solution and was collected through the bottom drain into a
coarse filter crock via vacuum filtration. The wet cake was
washed with 50/50 EtOH/H2O (1 L) and allowed to dry
overnight in the crock under a flow of N2. The wet cake was
air-dried in a glass tray to constant weight, over 7 d, to give
Supporting Information Available
This material is available free of charge via the Internet at
http://pubs.acs.org.
Received for review June 24, 2009.
OP9001577
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