Development and scale up of a route to cyclohexylhydrazine dimethanesulfonate

Article abstract of DOI:10.1021/op0002904

A mild, high-yielding synthesis of cyclohexylhydrazine dimethane-sulfonate has been developed that is suitable for further scale up. The process consists of three chemical steps: condensation of cyclohexanone with tert-butyl carbazate, reduction of the hy

Full text of DOI:10.1021/op0002904

Organic Process Research & Development 2000, 4, 526−529
Development and Scale Up of a Route to Cyclohexylhydrazine
Dimethanesulfonate
Terrence J. Connolly,* Andrew J. Crittall, Alkarim S. Ebrahim, and Guijun Ji
Raylo Chemicals Inc., A Laporte Fine Chemicals Company, 8045 Argyll Road, Edmonton, Alberta, T6C 4A9 Canada
Scheme 1a
Abstract:
A mild, high-yielding synthesis of cyclohexylhydrazine dimethane-
sulfonate has been developed that is suitable for further scale
up. The process consists of three chemical steps: condensation
of cyclohexanone with tert-butyl carbazate, reduction of the
hydrazone carboxylate to a hydrazine carboxylate with borane-
THF, and hydrolysis, decarboxylation, and derivatization with
methanesulfonic acid. From studies using a reaction calorimeter,
it was determined that the last stage of the process occurs in
two discrete steps, requiring 2 equiv of methanesulfonic acid.
The first equivalent of acid is consumed by N-protonation.
Deprotection of the Boc group occurs with the second equivalent
a Key: (a) tert-Butyl carbazate, hexanes, ∆; (b) H3B:THF, Na2CO3/NaCl/
H2O; (c) CH3SO3H, PhMe/THF.
of acid, as evident by the gas evolution. The heat of reaction
for the acid addition was determined to be 57.7 kJ/kg and
represents an adiabatic temperature rise of 27.4 °C.
under acidic conditions. Precipitation of the hydrazine as a
salt occurred concomitantly, and by-product formation was
not observed. Although the isolation methods and work-ups
developed by Venton were not particularly well-suited for
an industrial synthesis, his route was an attractive starting
point for process development. The process we developed
is shown in Scheme 1.
Introduction
The use of hydrazines as building blocks in the synthesis
of several heterocyclic systems is well documented.1 In
connection with a project under development, we required
significant amounts of cyclohexylhydrazine. Therefore, we
were interested in developing a route that would generate a
hydrazine derivative amenable to large-scale production and
long-term storage. This paper discusses our efforts towards
this goal.
A survey of the literature revealed several routes for the
synthesis of alkylhydrazines.2-7 One approach involves
condensation of methyl or ethyl carbazate with a carbonyl
compound, followed by hydrazone reduction, hydrolysis, and
decarboxylation. This method is not compatible with glass-
lined vessels due to the high temperature and strongly basic
conditions used for the hydrolysis and decarboxylation.
Additionally, there are reports of this method suffering from
sporadic yields and the formation of by-products that are
difficult to remove.3,5
Results and Discussion
Stage One: Hydrazone Formation. Our initial labora-
tory trials utilized heptane as the reaction solvent rather than
hexane as suggested by Venton. We reasoned that the higher
boiling point (98 vs 69 °C) of heptane versus hexane would
lead to a shorter reaction time. Heptane’s higher conductivity
(3 × 10-2 vs 1 × 10-5 pS m-1) was also attractive. Although
all processing equipment in our plants is grounded, safety
and hazards considerations dictate that the use of non-
conductive solvents be limited, especially when heteroge-
neous mixtures are present. High levels of electrostatic charge
can be generated during a solid/liquid-phase separation.
Insulating solvents can retain an electrostatic charge for long
periods of time, even when in contact with a grounded
surface.
Using heptane as the process solvent worked well,
providing the product hydrazone 1 in a yield of 80-85%.
However, the yield of 1 dropped from 85% to 54% when
the reaction time was increased from 4 to 16 h, indicating
product instability. Suspending pure, dry 1 in heptane and
agitating the resultant slurry under reflux conditions verified
product decomposition. Product recovery was only 85% after
5 h at reflux in heptane.
Venton improved the above-mentioned process by using
tert-butyl carbazate rather than methyl or ethyl carbazate.5
This modification allowed the hydrolysis to be performed
* Author for correspondence. Telephone: (780) 468-6060. Fax: (780) 468-
4784. E-mail: terry.connolly@raylo.laporteplc.com.
(1) Chemistry of Hydrazo-, Azo- and Azoxy Groups; Patai, S., Ed.; Wiley: New
York, 1975; Chapter 4.
(2) Audrieth, L. F.; Diamond, L. H. J. Am. Chem. Soc. 1954, 76, 4869.
(3) Chaco, M. C.; Stapp, P. R.; Ross, J. A.; Rabjohn, N. J. Org. Chem. 1962,
27, 3371.
(4) Gever, G.; Hayes, K. J. Org. Chem. 1949, 14, 813.
(5) Ghali, N. I.; Venton, D. L.; Hung, S. C.; Le Breton, G. C. J. Org. Chem.
1981, 46, 5413.
(6) Katritzky, A. R.; Rao, M. S. C. J. Chem. Soc., Perkin Trans. 1 1989, 2297.
(7) Katritzky, A. R.; Fan, W. J. Org. Chem. 1990, 55, 3205.
Hexanes was then evaluated as a reaction solvent on the
assumption that product decomposition was temperature-
dependent. Rapid conversion to the desired hydrazone
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10.1021/op0002904 CCC: $19.00 © 2000 American Chemical Society and The Royal Society of Chemistry
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occurred at reflux following suspension of tert-butyl carba-
zate and a slight excess of cyclohexanone in hexanes. The
reaction was complete within 3 h, and afforded product in
an average yield of 95%. Increasing the reaction time to 16
h caused the yield to decrease to 90%, which was signifi-
cantly better than the 54% yield observed after an equivalent
reaction time in heptane.
The conductivity issue mentioned earlier was addressed
by adding iso-propyl alcohol (10% w/w, relative to hexanes)
to the slurry prior to filtration. The presence of iso-propyl
alcohol did not adversely affect product recovery. Addition-
ally, the use of the more volatile hexanes rather than heptane
allowed us to dry hydrazone 1 on the filter to the point where
it contained less than 5% residual solvent (wt/wt basis). This
removed a drying step, further simplifying the operability
of the process since the amount of residual solvent that would
be carried forward to the next stage was negligible.
Stage Two: Hydrazone Reduction. Although Venton’s
procedure of adding a solution of borane-tetrahydrofuran
directly to the solid hydrazone would work on a small scale,
we found it more practical to suspend the hydrazone in THF
prior to charging the borane solution. Agitation of the
hydrazone slurry prior to the borane addition resulted in a
more even distribution of the borane solution as it was
charged. Adding a cold (5-10 °C) solution of the borane
complex and adjusting the addition rate to maintain the
reaction temperature controlled the exotherm of the reaction.
When the reduction was deemed complete, an aqueous
solution of sodium carbonate and sodium chloride was added.
This salt mixture quenched the residual borane complex,
extracted the boric acid into the aqueous layer, and led to
an organic layer that contained only 6% water (Karl-Fisher
method). Quenching the reaction with a solution of sodium
carbonate alone, followed by washing the organic layer with
a brine solution, was not effective in lowering the water
content of the organic layer. Decreasing the water content
was desirable since the final product, an ionic salt, was
suspected to have some water solubility. As well, we had
observed slow gas evolution from stock solutions of 2, which
was attributed to hydrolysis of the Boc group.
Following the aqueous work-up, the THF stock solution
of 2 was distilled under reduced pressure. One co-evaporation
with toluene, followed by dilution to the desired concentra-
tion, afforded a stock solution of hydrazinocarboxylate 2
containing 1.5% water (Karl-Fisher method) that could be
carried forward directly to the final stage of the process.
Stage Three: Hydrolysis, Decarboxylation, and De-
rivatization. Having developed a process that minimized the
amount of water carried forward to the final stage of the
process, we believed that using aqueous HCl as suggested
by Venton would result in a reduced yield of product. It was
determined that even use of concentrated HCl led to
significant product loss to the filtrate due to the water present
in the acid. It was anticipated that use of anhydrous HCl
would alleviate the problem of product loss to the mother
liquor. Addition of dry HCl to solutions of 2 in toluene or
heptane led to an exotherm that was difficult to control.
Additionally, the isolated product was a very non-granular,
pasty solid that was slow to filter, dried poorly, and entrained
a significant amount of HCl. Although a variety of solvents
and solvent mixtures were examined, the filterability of the
hydrazine salt was not improved.
A survey of other proton sources and solvents indicated
that methanesulfonic acid led to a derivative that filtered well
when 10% THF in toluene (wt/wt basis) was used as the
process solvent. Although using 1 equiv of methanesulfonic
acid led to poor recoveries, increasing the charge to 2 equiv
resulted in precipitation of the product as dimesylate salt 3
in excellent yield. The use of THF as a co-solvent was an
important parameter since product 3 filtered poorly when
isolated from neat toluene.
Although the process afforded good quality product 3 in
an overall yield of 90%, gas evolution did not appear to be
proportional to the dose of methanesulfonic acid. Initial lab
trials indicated that off-gassing did not start until the addition
of methanesulfonic acid was ∼30% complete. Increasing the
reaction temperature did not lead to an earlier onset of gas
evolution. If the reaction was showing an induction time, or
had mass flow characteristics that were not addition con-
trolled, then further scale up would be approached cautiously.
With a process that generated 2 equiv of gas per 1 equiv of
substrate, then factors such as vessel size, reactor headspace,
rating of the bursting disk, and vent design would need to
be considered carefully prior to scale up. On the basis of
these concerns, a reaction calorimeter study was done on
stage three of the process.
Reaction Calorimeter Study. Our concerns with stage
three centered on the observation of an exotherm and the
generation of significant quantities of isobutylene and carbon
dioxide. An experiment was conducted using a Mettler
Toledo RC1e calorimeter to establish the heat and mass flow
characteristics of stage three. In this experiment, 2 equiv of
methanesulfonic acid were added via a dosing loop to a
solution of 2 in THF/toluene. The addition of acid occurred
over 3 h while the calorimeter operated in a mode that
maintained the pot temperature at 25 °C.
The key data collected from the calorimeter study are
shown in Figure 1. The series labeled (Tr-Ta) represents the
difference between the pot temperature and the jacket
temperature. A positive value indicates that cooling was
applied to the reactor to offset a temperature rise due to an
exothermic reaction.
Figure 1 shows that the reaction was exothermic only
during the addition of the first equivalent of acid. After 1
equiv of acid was charged, the exotherm ceased, and gas
evolution started. Gas evolution steadily increased until it
reached a maximum that corresponded with the end of the
acid addition and then decreased immediately. When the gas
evolution was negligible, the reactor contents were adjusted
to 40-50 °C, and gas evolution was observed again. This
was attributed to dissolved gases, but the possibility exists
that the reaction did not go to completion until this extra
heating period was introduced.
The results of the calorimeter study were in conflict with
the observations made when this stage was conducted in a
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Figure 1.
20 L reactor. During lab trials, gas evolution was observed
after ∼30% of the acid had been added, whereas during the
calorimeter study, gas evolution started after 50% of the acid
had been added. The major difference between the two trials
was the time required for the methanesulfonic acid charge.
During the lab scale up, we charged 1.2 kg of acid over a
period of 3.5 h. When the experiment was conducted in the
calorimeter, 0.3 kg of acid was charged over 3 h. We believe
that the different feed rate of methanesulfonic acid was
responsible for the different observations made.
The calorimeter data indicates that the reaction occurred
in two discrete stages. Protonation of the nitrogen, which
was an exothermic reaction, occurred first. Once the first
equivalent of acid was consumed, then cleavage of the t-Boc
group occurred, as evident by the evolution of gas during
the charging of the second equivalent of methanesulfonic
acid. No exotherm is observed during the charge of the
second equivalent of acid, presumably because it is masked
by the endotherm associated with the generation of 2 equiv
of gas.
On the basis of our studies, it appears that rapid addition
of methanesulfonic acid resulted in some accumulation of
acid. Although it is possible that the first protonation step is
slow, it is more likely that slow diffusion of the acid through
the reaction mixture resulted in a localized accumulation that
allowed the hydrolysis and decarboxylation to occur before
all of 2 had been protonated.
One important observation from the calorimeter study was
that both the exotherm and gas evolution were proportional
to the dose of methanesulfonic acid. With respect to further
scale up, this addition control of both pot temperature and
pressure are attractive features of this process.
Conclusions
A simple, high-yielding, streamlined process has been
developed for the large-scale preparation of a dimethane-
sulfonate salt of cyclohexylhydrazine. Key points in the
development were the use of hexanes as a solvent for stage
one, which resulted in a robust hydrazone-forming process.
Suspension of the hydrazone in THF, followed by addition
of borane-THF resulted in the smooth formation of the stage
two hydrazino carboxylate. The aqueous work up removed
boron residues and afforded an organic layer that could be
dried azeotropically during the solvent switch from THF to
toluene. Finally, a reaction calorimeter study provided
detailed information with respect to the reaction mechanism,
mass, and energy flow of the final stage of the process. It
was determined that both the exotherm and gas evolution of
the last stage were proportional to acid dose. Control of both
the reaction temperature and reactor pressure would be easily
achieved upon further scale up by adjusting the acid feed
rate.
Experimental Section
tert-Butyl carbazate (800 g, 6.05 mol, 1.0 equiv.),
cyclohexanone (713 g, 1.2 equiv), and hexanes (2.0 kg) were
charged to a 10 L reactor. The resulting slurry was heated
to reflux, and water was removed via a Dean-Stark trap.
After 3.5 h at reflux, TLC (3% MeOH in DCM, phospho-
molybdic acid (PMA) dip and char for visualization)
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indicated that the reaction was complete. The slurry was
cooled to 0-5 °C and agitated for ∼1 h, and 2-propanol
(0.2 kg) was added. The slurry was filtered and the reactor
rinsed forward with the filtrate until free of solids. The filter
cake was pulled dry for ∼30 min and then discharged to yield
1.26 kg of hydrazone 1 (98.4% of theory). The hydrazone
was charged to a 20 L reactor, followed by 1.26 kg of THF
to affect a slurry. Agitation was started and borane-THF
(1.0 M in THF, 6.52 kg, 1.2 equiv) was added over ∼1 h.
As the reaction progressed, the slurry became a clear
homogeneous solution. Over the course of the addition, a
temperature rise of 15 °C was noted (start temp ) 16 °C,
final ) 31 °C), no external cooling was applied. The solution
was then adjusted to 40-60 °C for 1 h, then cooled to 20
°C. A solution of Na2CO3 (770 g, 1.2 equiv) and NaCl (707
g, 2.0 equiv) in water (6.93 kg) was slowly charged
(Caution: Strong gas evolution in the beginning) and the
resulting bi-phasic solution was agitated at room temperature
for 1 h. The layers were separated, and the organic layer
was concentrated under reduced pressure until distillation
stopped. Toluene (1.9 kg) was charged to the slurry and the
vacuum distillation repeated (maximum pot temperature 43
°C). Toluene (2.88 kg) and THF (320 g) were charged to
the residue, and the contents were adjusted to 20 °C.
Methanesulfonic acid (1.16 kg, 2.0 equiv) was added over
3.5 h (Caution: Exotherm and strong gas evolution)
during which time there was an exotherm of 21 °C. After
the addition, the reaction mixture was adjusted to 40 °C until
gas evolution ceased. The slurry was then cooled to 0-5
°C, agitated for 1-2 h, and filtered, rinsing the reactor
forward with the filtrate. When all of the solids were rinsed
from the reactor, the reactor and cake were rinsed twice with
10% THF/toluene (250 mL each). The cake was pulled as
dry as possible and then discharged, yielding 2.41 kg of the
product as a wet cake. A sample of the cake was analyzed
for loss on drying, and the corrected yield of the dimesylate
was determined to be 89.7% from tert-butyl carbazate (31%
LOD).
which was equipped with a pH probe, pot temperature sensor,
glass baffles, a down-flow propeller agitator, a calibration
heater, gas flowmeter, and a dosing pump with dosing tip
sensor. The agitation was ramped from 100 to 650 rpm over
5 min. Cyclohexylhydrazine carboxylate (300 g) was charged
to the reactor, the temperature was adjusted to 25 °C, and a
calibration was performed to determine the heat-transfer
coefficient. Methanesulfonic acid (305 g) was added via a
dosing loop over 3 h. At the end of the addition when gas
evolution had subsided, the temperature was increased to 45
°C at a rate of 2 °C/min. The contents were held at that
temperature until the flow of off-gas decreased ( ∼15 min)
and then were cooled to 5 °C prior to discharging the reactor
contents. The RC-1 was interfaced with a Dell P11233
computer, and all data were collected and analyzed using
the WinRC software package.
Product Characterization. tert-Butyl cyclohexylidene
1
hydrazinocarboxylate (1): H NMR (CDCl3, 200 MHz) 1.46
(s, 9H), 1.60 (m, 6H), 2.19 (t, J ) 6.20 Hz), 2.32 (t, J )
6.20 Hz), 7.57 (s, 1H); mp 136.4-136.7 °C, lit. 134-135
°C.5
1
tert-Butyl cyclohexylhydrazinocarboxylate (2): H NMR
(CDCl3, 200 MHz) 1.15 (m, 6H), 1.45 (s, 9H), 1.75 (m,
5H), 2.75 (m, 1H), 6.10 (br, 1H) ppm; mp 80.5-81.7 °C,
lit. 76-78 °C.8
Cyclohexylhydrazine dimethansulfonate (3): 1H NMR
(DMSO, 200 MHz) 1.10 (m, 6H), 1.75 (m, 4 H), 2.40 (s,
6H), 2.85 (m, 1H), 8.65 (br, 5H) ppm. Elemental analysis:
Calcd (found): 31.36 (29.28) %C, 7.24 (7.13) %H, 7.99
(9.14) %N, 20.93 (19.21) %S.
Acknowledgment
We are grateful to Dr. Robin Nicol for his critical review
of this manuscript and to the reviewers for their constructive
comments.
Received for review July 13, 2000.
OP0002904
Reaction Calorimeter Experiment. Toluene (1200 g)
and THF (83 g) were charged to a Mettler Toledo RC1e,
(8) Baumgarten, H. E.; Chen, P. Y.-N.; Taylor, H. W.; Hwang, D.-R. J. Org.
Chem. 1976, 3805.
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