Overcoming Problems at Elaboration and Scale-up of Liquid-Phase Pd/C Mediated Catalytic Hydrogenations in Pharmaceutical Production

Article abstract of DOI:10.1021/acs.oprd.6b00073

The practical solutions for scale-up and production of intermediates or precursors of pharmaceuticals by liquid-phase Pd/C mediated hydrogenation can be of considerable interest and deserve broader attention even if they have not been the focus of previously published research due to regulations of patent law. The practical obstacles are persistent and have been known for a long time, but for the most part remained unpublished. The most important discoveries and solutions that contributed to the successful scale-up of hydrogenations for pharmaceutical production were the following: (i) the poisoning of Pd/C catalyst with Fe²⁺ ions for the selective hydrogenation of 2,6-dimethyl-1-nitrosopiperidine to the corresponding hydrazo compound; (ii) alloying of the deposited Pd metal with Cu for converting the aromatic acid chlorides into the corresponding aldehydes; (iii) alteration of the pH of the reaction mixture to basic values which enhanced the stereoselectivity of paracetamol hydrogenation; (iv) a useful modification of the catalyst preparation process, i.e., the acidification of the catalyst resulted in the hydrogenolysis of benzylic OH in a molecule containing a basic N atom; (v) use of two liquid phases, altogether a four-phase system, which permitted the hydrogenolysis of the S-S bond in a potential catalyst poisoning molecule; (vi) the preservation of the metallic Pd surface of the catalyst by saturation of the reaction mixture with hydrogen, resulting in a high H₂/substrate ratio, increased the aldehyde yield in the hydrogenation of 4-chloro-butyric-acid-chloride by avoiding the unwanted poisoning effect of the hydrochloric acid. In the present article, these problems and their solutions, as they emerged during the scale-up of the processes, will be discussed in detail.

Full text of DOI:10.1021/acs.oprd.6b00073

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Full Paper
Overcoming problems at elaboration and scale-up of liquid phase Pd/
C mediated catalytic hydrogenations in pharmaceutical production
Antal Pál Tungler, and Erika Szabados
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00073 • Publication Date (Web): 03 Jun 2016
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Organic Process Research & Development
Overcoming problems at elaboration and scaleꢀup
of liquid phase Pd/C mediated catalytic
hydrogenations in pharmaceutical production
"Work from the Organic Reactions Catalysis Society meeting 2016"
Antal Tungler†*, Erika Szabados†
*Budapest University of Technology and Economics, Department of chemical and
Environmental Process Engineering,1111 Budapest, Hungary, Budafoki út 8.
†Hungarian Academy of Sciences, Centre for Energy Research, Surface Chemistry and Catalysis
Department, 1121 Budapest Hungary, KonkolyꢀThege Miklós út 29ꢀ33,
tungler.antal@energia.mta.hu
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KEYWORDS: multipleꢀphase catalytic hydrogenation, Pd/C, pharmaceutical production,
overcoming scaleꢀup problems
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ABSTRACT
The practical solutions for scaleꢀup and production of intermediates or precursors of
pharmaceuticals by liquid phase Pd/C mediated hydrogenation can be of considerable interest
and deserve broader attention even if they haven’t been the focus of previously published
research due to regulations of patent law. The practical obstacles are persistent, and have been
known for a long time, but for the most part remained unpublished. The most important
discoveries and solutions that contributed to the successful scaleꢀup of hydrogenations for
pharmaceutical production were the following : (i) the poisoning of Pd/C catalyst with Fe2+ ions
for the selective hydrogenation of 2,6ꢀdimethylꢀ1ꢀnitrosopiperidine to the corresponding hydrazo
compound; (ii) alloying of the deposited Pd metal with Cu for converting the aromatic acid
chlorides into the corresponding aldehydes; (iii) alteration of the pH of the reaction mixture to
basic values which enhanced the stereoselectivity of paracetamol hydrogenation; (iv) a useful
modification of the catalyst preparation process, i. e. the acidification of the catalyst resulted in
the hydrogenolysis of benzylic OH in a molecule containing a basic N atom; (v) use of two
liquid phases, altogether a fourꢀphase system, which permitted the hydrogenolysis of the SꢀS
bond in a potential catalyst poisoning molecule; (vi) the preservation of the metallic Pd surface
of the catalyst by saturation of the reaction mixture with hydrogen, resulting in a high
H2/substrate ratio, increased the aldehyde yield in the hydrogenation of 4ꢀchloroꢀbutyricꢀacidꢀ
chloride by avoiding the unwanted poisoning effect of the hydrochloric acid. In the present
article these problems and their solutions, as they emerged during the scaleꢀup of the processes,
will be discussed in detail.
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Introduction
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Catalytic threeꢀphase hydrogenation processes are important steps in the production of basic
chemicals, intermediates and fine chemicals. The success story of hydrogenation started more
than one hundred years ago with the work of Sabatier1 and still goes on. These liquidꢀphase
hydrogenations are carried out under relatively mild conditions. Their atom economy and
selectivity are high for conversion of molecules having easily reducible functional groups. In the
late 1960’s despite of the very limited availability of information from the West our university
library in Hungary had the books written by Augustine2, Freifelder3 and Rylander4. However
most of the knowledge with respect to the practical, primarily industrial scale, application of
hydrogenation remained hidden in the databases of the chemical companies. It is worth
mentioning that one of the big German chemical firms during the above mentioned period
collected and listed several thousand recipes used in hydrogenation reactions5 in the period from
the introduction of catalytic hydrogenation into production activities (early 1900’s) until 1976.
The intention of this paper is to publish some practical “knowꢀhow” information utilized in the
scaleꢀup of liquid phase Pd/C mediated hydrogenation processes for production of intermediates
or precursors of pharmaceuticals. All of these were worked out more than 20 years ago, so their
publication now doesn’t harm any interests. The hydrogenations discussed in the following case
studies were developed during those times when no product patents existed in the Soviet bloc
countries and the new drug molecules invented and licensed anywhere in the world were copied
and produced. The only requirement was that the synthesis method had to be independent and
patentable. Production of generic drugs in Hungary required newly developed syntheses since
the companies in the Western countries tried to block their synthesis routes by patent protection.
The simple but inventive solutions were stimulated not only by the need for new processes with
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increasing selectivity and yield, but also by the necessity that was the consequence of poor
technical conditions, e.g. a shortage of special industrial devices like high pressure, well stirred
autoclaves. A practice that helped greatly in the birth of these inventions was a permanent
cooperation between academic and industrial research based on mutual trust, which is unusual
nowadays. The industrial partners shared classified information and all necessary materials and
analytical methods in order to achieve the desired results quickly.
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Are the solutions reviewed in the following case studies outdated or still relevant? Searching
the literature resulted in finding only one paper describing the selective hydrogenation of acid
chlorides with a Pd/C catalyst using acetone or ethyl acetate as solvent and
ethyldiisopropylamine as hydrogen chloride acceptor6. The reactions were carried out at
millimolar scale, with relatively high catalyst/substrate ratio. There was no hint about scaleꢀup,
but difficulties could be expected to emerge because the amineꢀhydrochloric acid salt formed is
insoluble in the solvents used.
During the past decades, the hydrogenation apparatus became more advanced. Besides the
traditional batch autoclaves, the use of loop reactors is now also prevalent. The applicable
temperature and pressure ranges are now much wider (operating at pressures up to 200 bar and
temperatures up to 300 °C). One can choose among several different types of impellers, with
magnetic drive, or gas suction capability. The catalyst manufacturers offer a large assortment
with different compositions, supports, dispersions, so that a user can choose the best catalyst for
the particular purpose. Among the commercial catalysts there are also wet versions, usually with
50% water content. Nevertheless, the examples resulting from our earlier work can be
instructive, despite the huge progress of hydrogenation technologies and the new apparatus that
were marketed in the last decades.
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Experimental Section, Materials and Methods
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The Pd catalysts used in the majority of the hydrogenations that are discussed in the following
case studies were the 5 and 10 wt% Pd on high surface area (>1000 m2/g) activated carbon. They
were produced in Hungary under the trade name SELCAT by the late Finomvegyszer
Szövetkezet (today its successor is Szilor kft [Ltd], http://szilor.hu/termekkategoria/egyebꢀ
termekek/), according to a patented process developed in our laboratory6. The main steps of the
catalyst preparation process are shown in Scheme 1. They are (i) the deposition of the Pd
precursor with a tetraalkylammonium compound onto the activated carbon, (ii) basification with
KOH forming Pd(OH)2, (iii) its hydrogenation to metallic Pd, and finally (iv) washing to neutral
and optional drying. The SELCAT catalysts were compared in large scale hydrogenations with
other commercial catalysts (from Engelhard, Degussa, Heraeus, AMCPMC, J&M, Montedison),
and show better or commensurable activity and selectivity.
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The great advantage of our own catalyst preparation process was the possibility of making
modifications according to the actual requirements of the planned hydrogenation process. One of
the modification methods was the acidification of the reduced and washed catalyst with an
aqueous solution of acetic acid or sulfuric acid.
In this way the remaining trimethylamine
content of the Pd/C catalyst prepared according to the above described method became
protonated. A further modification procedure was the repeated hydrogenation of the catalyst
prior to and after acidification. The introduction of a second metal, primarily copper, could be
carried out during the preparation procedure by coꢀdeposition of the Pd and Cu precursors 8.
Scheme 1. The reaction scheme of the Pd/C catalyst preparation
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CH3
CH3
4 KOH
H3C N+ CH3
Cl-
H3C N+ CH3
+
2
2
K2PdCl4
C
+
PdCl4
2
C +
2 KCl
H2C
Ph
H2C
Ph
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CH3
H3C N+ CH3
2 H2
OH-
+
4 KCl
2 C6H5-CH3 4 H O
+
+
2 (CH ) N
Pd(OH)2
C
+
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+
2
3 3
H2C
Ph
The labꢀscale process hydrogenations were done at ambient conditions in glass flasks placed
on a shaking machine or with magnetic stirrers. The consumed hydrogen was measured with gas
burettes. Those laboratory scale processes performed under high pressure and at elevated
temperatures were tested in autoclaves (Autoclave Engineers, Büchi) that were equipped with
magnetically driven gas suction and dispersing turbo stirrers. The reaction mixtures were
analyzed with gas chromatographic (GC) and high performance liquid chromatography (HPLC)
methods carried out by the cooperating partners.
An important element of our activity was to reconcile the mixing properties of our laboratory
apparatus with those of the available industrial autoclaves in order to avoid low yields and/or
poor selectivity and other disappointments during scaleꢀup. The majority of the industrial devices
were equipped with slipꢀring sealing, but could be used only up to 6 bar pressure. Their mixing
impellers were the soꢀcalled anchor type with revolution speeds below 120 minꢀ1. For the more
effective entrainment of the gas into the liquid, a thermometer socket or a blade was immersed in
the liquid phase to function like a static mixer and thereby increase turbulence.
Results and discussion
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The following case studies discuss six scaledꢀup hydrogenations for the reactions shown in
Schemes 2ꢀ7, which show the substrates and the products. The selected examples are the most
instructive ones with respect to the solutions we developed and their results. The methods
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reviewed here were used for other substrates as well8, 9, 10
.
Case 1 Modified solvent and modified selective poisoning of the catalyst
Scheme 2. Hydrogenation of 2,6ꢀdimethylꢀ1ꢀnitrosopiperidine
H2
H2O
2 H2
+
+
NH3
+
N
H3C
CH3
N
H3C
CH3
N
H
H3C
CH3
NH2
NO
Selective hydrogenation of the secondary Nꢀnitroso amines, such as the 2,6ꢀdimethylꢀ1ꢀ
nitrosopiperidine, to the corresponding hydrazo compound with 90% yield was invented in the
sixties11. At the lab scale the catalyst was poisoned by adding Fe2+ ions to the Pd/C, the solvent
was ethanol (Scheme 2), and the original production specification could be easily reproduced.
The biggest obstacle we had to face was that 40 bar of hydrogen pressure was necessary for the
desired yield. This was practicable on laboratory scale, but our partner company had autoclaves
working only up to 6 bar pressure. The reaction didn’t work at all at 6 bar, and if we increased
the temperature the selectivity became worse. In the original recipe FeCl2 was used as the
selective poison.
We had an earlier experience that the selective hydrogenation of 2ꢀmethylindole to 2ꢀ
methyilindoline could be carried out in the presence of sulfuric acid and KCl. Without KCl the
reaction proceeded until the octahydro compound. Based on this, instead of FeCl2, we used
FeSO4 for the selective poisoning. An aqueous solution of FeSO4 was added to the reaction
mixture together with the catalyst and the substrate and the solvent was 10 wt% NH3 in water.
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The NH3 was beneficial for the selectivity, as it retarded the hydrogenolysis of the amino group
of the desired product. The hydrogenation could now be carried out at ambient temperature and 3
bar hydrogen pressure. The hydrazo product could be separated by vacuum distillation with a
yield that was only 10% lower than in the original patent description, and soon the production
started on a commercial scale.
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Case 2 Alloying the Pd with Cu for the Rosenmund reaction
The Rosenmund reduction12, 13, 14 seemed to be a promising option for the preparation of some
aromatic aldehydes since the starting carboxylic acids were easily available (Scheme 3). But the
poisoning of the Pd/BaSO4 catalyst with sulfur compounds couldn’t be carried out on a larger
scale, and moreover, the activity of this type of catalyst was not sufficient for feasible
production. Use of a Pd/C catalyst combined with HCl scavengers (hindered secondary amines)
and mild catalyst deactivators (thioanisole) produced Nꢀprotected piperidine carboxaldehyde for
secretagogue MKꢀ677 (of Merck) synthesis with an excellent yield in kg scale experiments13.
Siegel et al published a review about the Rosenmund processes used in the pharmaceutical
production14, among others about how 3,4,5ꢀtrimethoxyꢀbenzaldehyde was prepared similarly
but with Naꢀacetate as HCl scavenger15.
Scheme 3. Selective hydrogenation of aromatic acid chlorides
COCl
COH
Pd-Cu/C
X = methoxy, hydroxy, acetoxy
HCl
H2
+
+
(X)n
(X)n
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The application and investigation of bimetallic catalysts was a popular topic in the 1970’s. A
PdꢀCu/C catalyst proved to be highly efficient in the selective C=C hydrogenation of a
tetracycline derivative, without hydrogenolysis of an OH group, so it was also tested in acid
chloride hydrogenations. The introduction of 13 atomic% Cu into the Pd/C catalyst was optimal
for the Rosenmund reduction. The selectivity towards substituted aromatic aldehydes was around
90% and there was sufficient activity. The solvents were toluene or xylene, and hydrogen was
bubbled through the vigorously stirred reaction mixture at 80 °C.
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The reduction of 3,4,5ꢀtrimethoxybenzoic acid chloride was successful at labꢀscale in a 2 L
volume and the yield of the prepared aldehyde was around 80%. But the scaleꢀup in a 1000 L
autoclave failed. The aldehyde formation stopped at around 30% conversion and the nonꢀ
selective hydrogenation to trimethoxytoluene dominated together with water formation.
Subsequently the acyl chloride decomposed mainly to the acid that precipitated from the
aromatic solvent. Since the PdꢀCu/C catalyst sample used for the scaledꢀup process was
previously tested and worked properly in labꢀscale experiments, the reason for the malfunction of
the large scale system was not clear. The explanation (namely the deficiency of hydrogen and
HCl poisoning of the surface of the catalyst) was found years later and will be presented in Case
6.
Case 3 The effect of adjusting of the pH on stereoselectivity
The preparation of transꢀ4ꢀacetylamino cyclohexanol was crucial in ambroxol (ambroxol is
transꢀ4ꢀ(2ꢀaminoꢀ3,5ꢀdibrombenzylamino)ꢀcyclohexanol) synthesis. The reaction was first
performed with Adams’ platinum catalyst, and the stereoselectivity of the trans product was only
40 %. After we acquired some experience in the stereoselective Pd mediated hydrogenation of
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thymol16, an analogous solution seemed to be promising to increase the yield of the trans product
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of the aboveꢀmentioned reaction.
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Scheme 4. Stereoselective hydrogenation of Nꢀ(4ꢀhydroxyphenyl)acetamide
OH
H2
2 H2
NHCOCH3
NHCOCH3
OH-
Pd/C OH- water
HO
O
NHCOCH3
trans-4-acetylamino cyclohexanol
1 wt% potassium acetate (which is already present in a small amount in the SELCAT catalysts,
being formed during the final washing procedure with acetic acid), was added to the water
solvent to adjust the pH to around 10. The substrate solubility was low, and the reaction was
o
completed within 5 hours at 105 C and at 6 bar pressure. The low solubility was advantageous,
because it resulted in a larger catalyst/substrate ratio in the solution. In a pilot scale experiment
using a 1000 L autoclave at 6 bar pressure and 110 oC with a Pd/C catalyst (10 wt% metal on the
support, giving a substrate: catalyst ratio of 100:1) the reaction was completed within 6 hours,
and the stereoselectivity towards transꢀ4ꢀacetylamino cyclohexanol was 80 % according to GC
analysis. The reaction mixture was evaporated and the remaining oil recrystallized from the
acetone giving the trans product in pure form with 60% yield. The explanation for the higher
stereoselectivity and yield is the following: the intermediate transꢀketo product has two forms:
the acetylamino group in the equatorial or in the axial position. The keto compound containing
the acetylamino group in the equatorial position can be adsorbed on the catalyst surface more
easily. If the reduction of this form results in the equatorial alcohol ꢀ which is preferred in a basic
solution16ꢀ, the product will be preferentially the transꢀstereoisomer (Scheme 4).
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Case 4 The effect of acidification of the catalyst on chemoselectivity
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In the hydrogenation of an intermediate keto compound of enalapril synthesis (enalapril is (2S)ꢀ
1ꢀ[(2S)ꢀ2ꢀ{[(2S)ꢀ1ꢀethoxyꢀ1ꢀoxoꢀ4ꢀphenylbutanꢀ2ꢀyl]amino}propanoyl]pyrrolidineꢀ2ꢀcarboxylic
acid, which is an angiotensinꢀconvertingꢀenzyme inhibitor) the complete hydrogenolysis of one
of the carbonyl groups was necessary (Scheme 5).
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Scheme 5. Hydrogenation of the enalapril precursor
O
COOEt
O
CH3
EtOOC
NH
O
N
NH
CH3
HOOC
H2
H2O
+
+
N
HOOC
The hydrogenation to OH of the keto carbonyl group in the benzylic position can be completed
at room temperature and atmospheric pressure within an hour with Pd/C. The basic N atom in the
molecule inhibits the cleavage of the hydroxyl group, so the reaction stops at the intermediate
stage.
The researchers of the interested partner in the laboratory scale experiments acidified the dry
Pd/C catalyst with a 10 wt% sulfuric acid solution. The catalyst material was suspended in the
acidic solution, mixed for some seconds, filtered off and washed with distilled water on a glass
filter. This procedure required altogether one minute. Then they put the pretreated catalyst into
the reaction mixture. By applying this catalyst pretreatment procedure, not only the
hydrogenation of the keto carbonyl group but also the concomitant hydrogenolysis of the OH
was completed. When they tried to scaleꢀup the procedure, instead of 2 g of catalyst, 5 kg of
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Pd/C had to be treated with sulfuric acid solution, and the completion of the acidification process
required approximately 1 hour. Moreover, the subsequent washing with deionized water also
took several hours, during which the catalyst lost 90% of its Pd content. In other words, the
catalyst deactivated. This leaching was the consequence of the presence of a highly dispersed Pd
surface covered by adsorbed oxygen which could not resist the corrosion caused by the acidic
environment.
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This problem could be solved by a modification of the SELCAT catalyst preparation process7.
After the reduction step and the washing of the catalyst with deionized water on a centrifuge, it
was suspended in water again in the enameled hydrogenation reactor, hydrogenated again, and
then the sulfuric acid solution was added to the mixture and the hydrogenation repeated. The
resulting acidic mixture was filtered and the catalyst was washed with deionized water, and
finally dried. The catalyst prepared in this way was very active, the hydrogenation and the
hydrogenolysis processes using it were complete, and there was no Pd loss.
Case 5 Multi-phase (four) reaction mixture
In the synthesis of another angiotensinꢀconvertingꢀenzyme inhibitor captopril ((2S)ꢀ1ꢀ[(2S)ꢀ2ꢀ
methylꢀ3ꢀsulfanylpropanoyl]pyrrolidineꢀ2ꢀcarboxylic acid), the final step was a reduction, giving
the active substance. The precursor substrate was a disulfide, in which the SꢀS bond had to be
hydrogenolyzed (Scheme 6).
Scheme 6. Hydrogenolysis of the SꢀS bond yielding captopril
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O
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In the first attempt, the reduction was carried out with Zn in an acidic aqueous solution. The
formed captopril was extracted with dichloromethane, which is an excellent solvent of captopril.
However, neither the yield nor the purity of the product was satisfactory. The catalytic
hydrogenation seemed to be rather difficult as both the substrate and the product were strong
poisons for Pd catalysts. In spite of this, the hydrogenation could be carried out in water with 10
wt% Pd/C catalyst at 80 oC and 6 bar, but the filtered reaction mixture contained impurities, had
a dark color and the captopril extracted with dichloromethane couldn’t be purified to the desired
degree.
The small, but important change during the first successful laboratory experiments was that
besides water, dichloromethane, which is nonꢀmiscible with water, was added as a second
solvent, forming a fourꢀphase reaction mixture. Most of the hydrogenated product went into the
organic phase during and after the completion of the reaction. The product, after recrystallization
from ethyl acetate, contained less than 0.1% starting material and the yield was above 80%. This
specification satisfied even the requirements of the FDA, and therefore the product was
distributed in the USA as well. The product yield and quality could be further improved after the
collaborating partner purchased a 1000 L autoclave with magnetically driven gasꢀdispersing
stirrer that was capable to working up to 100 bar pressure.
Case 6 Continuous feed of the substrate in batch reaction
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This study dealt with the first step in the Fischerꢀtype synthesis of tryptamine, 2ꢀ(1HꢀIndolꢀ3ꢀ
yl)ethanamine), which is the preparation of 4ꢀchloroꢀ1ꢀbutanal by a Rosenmundꢀtype reaction
(Scheme 7). The trivial name for this product is 4ꢀchloroꢀbutyraldehyde.
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This version of the Fischerꢀtype synthesis of indol derivatives17, among others that of
tryptamine, was first described by Russian scientists18ꢀ21. In the lab scale process, the starting
material of this Rosenmund type hydrogenation, 4ꢀchlorobutyric acid chloride, can be prepared
in a simple process from 4ꢀbutyrolactone by chlorination using phosgene. The 4ꢀchloroꢀ
butyraldehyde was then prepared in toluene from the acid chloride by hydrogenation. The
aldehyde was reacted with phenylhydrazine in a condensation reaction during cooling, resulting
in the hydrazone. Then methanol and the aqueous solution of Naꢀacetate was added, the reaction
o
mixture was heated to 95ꢀ100 C and stirred vigorously for 6 hours in an autoclave under a N2
atmosphere. The hydrochloride salt of tryptamine was prepared from the aqueous phase after
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evaporating the methanol content and cooling the solution to 5 C. In the original description of
the laboratory scale process the yield of tryptamine was above 50%. In the plantꢀscale production
with the same procedure the yield of tryptamine was less (~35%) and strongly depended on the
aldehyde, the remaining acid chloride content and the amount of side products of larger
molecular weight in the hydrogenation reaction mixture.
Scheme 7. Hydrogenation of 4ꢀchloro butyric acid chloride
O
O
Cl
Cl
HCl
H2
+
+
Cl
H
A nonꢀmodified SELCAT Pd/C catalyst was used in this hydrogenation, because this aliphatic
acid chloride could be selectively reduced to the corresponding aldehyde, avoiding poisoning.
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The tryptamine yields in the laboratory experiments were much higher than in the large scale
production, and we finally concluded that the difference was primarily in the conditions of the
hydrogenation. Both in the laboratory and in the plant size equipment H2 was bubbled through
the hydrogenation reaction mixture under intensive stirring. The difference was in the specific H2
flow; in the 1 L laboratory flask 20ꢀ25 L hourꢀ1 was used. Scaling up this value for a 1000 L
autoclave meant 20000ꢀ25000 L hourꢀ1 H2 which couldn’t be implemented. The attempt to
increase the H2 stream failed. The strong gas bubbling, together with the stirring generated
strong vibrations which would have disintegrated the autoclave. The high H2 flow caused another
problem, namely purging out drops of the reaction mixture. As a result, the return condenser was
overloaded and flooded soon after the operation started. The tolerable gas flow was around 5000
L hourꢀ1. Another reason why the procedure used during the labꢀscale synthesis could not be used
at plant scale was that adding the total amount of acid chloride into the reaction mixture at one
time caused an increase in the HCl concentration in the reaction mixture, which resulted in the
poisoning of the Pd. In order to avoid the deactivation of the catalyst by HCl, a compromise was
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used. The catalyst was preꢀsaturated with H2 in toluene at 80 C and the acid chloride solution
was fed at a suitable rate from another autoclave under N2 overpressure. The smaller H2 flow
removed the HCl formed at the lower rate and the catalytic activity could be preserved.
With this scaledꢀup arrangement (Scheme 8) the aldehyde content of the hydrogenated
reaction mixture increased and the tryptamine yield improved to above 60%, approaching the
laboratory results (65%).
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Scheme 8. The arrangement used for the hydrogenation of 4ꢀchloro butyric acid chloride
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Conclusion
The most important practical solutions that permitted the scaleꢀup of hydrogenations for
pharmaceutical production were the follows: (i) the partial poisoning and alloying (with Cu) of
the Pd/C catalyst in order to increase the selectivity, (ii) adjusting the pH of the reaction mixture
by utilizing the effect of bases in stereoselective hydrogenation of the keto group in cyclic
compounds, (iii) the proper modification of the catalyst preparation process, treatment of the
catalyst with acids, in a particular case together with its repeated saturation with H2, (iv) use of
two liquid phases, water and an apolar solvent, immiscible with water, giving a fourꢀphase
systems, and transferring the substrate and/or the product into one of them, (v) the protection of
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the Pd catalysts preserving the metallic surface, keeping it saturated with hydrogen, ensuring the
high H2/substrate ratio, avoiding the unwanted poisoning by hydrochloric acid.
In several cases, the scale up of these hydrogenations helped a few members of the Hungarian
pharmaceutical industry to produce and sell their important pharmaceuticals, primarily in Eastern
Europe.
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The results also served as a basis for further R&D.
AUTHOR INFORMATION
Corresponding Author
*Antal Tungler, MTA EK, 1121 Budapest Hungary, Konkoly Thege Miklós út 29ꢀ33,
tungler.antal@energia.mta.hu
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
ACKNOWLEDGMENT
The authors are grateful to MTA EK and BME for supporting the creation of this paper and to
Professor Jesse L. Weil, József S Pap, PhD and Ferenc Somodi, PhD for fruitful discussions.
REFERENCES
1. Sabatier, P.: La catalyse en chimie organique (Paris, 1913: 2nd ed., 1920).
2. Augustine, R. L: Catalytic Hydrogenation,Techniques and Applications in Organic Synthesis,
Dekker, NY, 1965.
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3. Freifelder, M.: Practical Catalytic Hydrogenation, Wiley, NY, 1971.
4. Rylander, P. N.: Catalytic Hydrogenation over Platinum Metals, Academic Press, NY, 1967.
5. Arpe, H. J.: Personal communication 1976.
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44
45
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6. Peters, J. A. van Bekkum, h., Recueil des Travaux Chimiques des Pays-Bas, 1981, Volume
100, Issue 1, pages 21–24.
7. Máthé, T., Tungler, A., Petró, J.: Hung. Patent 177 860, USA Patent 4.361.500.
8. Petró, J., Máthé, T., Tungler, A., Csűrös, Z.: Hungarian Patent.168 073, USA Patent.
4 021 376
9. Máthé, T., Tungler, A., Petró, J.: Hungarian Patent 178 872.
10. Tungler, A., Tarnai, T., Hegedűs, L., Fodor, K., Máthé, T.: Platinum Metals Rev., 1998, 42,
(3), 108ꢀ115.
11. Tuemmler, W. B., Winkler, H. J. S., USA Patent 2979505 A
12. Rosenmund, K. W., Chemische Berichte, 51, 585ꢀ593, 1918,
13. Maligres, p., E., Houpis, I., Rossen, K., Molina, A., Sager, J., Upadhyay, V., Wells, K., M.,
Reamer, E., A., Lynch, J., E., Askin, D., Volante, R., P., Reider, P., J., Tetrahedron, Vol. 53, No.
32, pp. 10983ꢀ10992, 1997.
14. Siegel, S., King, A. O., Shinkai, I., www. reag.paperplane.io/00002155.htm 2000
15. Wagner, D. P., Gurien, H., Rachlin, A. I., Ann. N. Y. Acad. Sci. 1970, 172, 186.
16. Tungler, A., Máthé, T., Bende, Z., Petró, J.: Appl. Catal. 19, 365ꢀ374, (1985).
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17. Evins, A. J., J. Chem. Soc. 99, 270 (1911).
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18. Grandberg, I. I., Bobrova, N. I., Khim. Geterotsikl. Soedin., 213 (1973). [Chem. Heterocycl.
Сотр., 9, 196 (1973)].
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19. Grandberg, I. I., Bobrova, N. I., Syntheses of Heterocyclic Compounds [in Russian], Iss. 9,
Izd. Akad. Nauk ArmSSR, Erevan (1972), p. 18.
20. Grandberg, I. I., Bobrova, N. I., Khim. Geterotsikl. Soedin., 1085 (1974). [Chem. Heterocycl.
Сотр., 10, 943 (1974)].
21. Grandberg, I. I., Zuyanova, T. I., Afonina, N. I., Ivanova, T. A., Dokl. Akad. Nauk, 176, 583
(1967).
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