A DMAP-catalyzed approach to the industrial-scale preparation of N -6-demethylated 9,10-dihydrolysergic acid methyl ester: A key cabergoline and pergolide precursor

Article abstract of DOI:10.1021/op500394f

A scalable new approach for the preparation of N-6-demethylated 9,10-dihydrolysergic acid methyl ester using 2,2,2-trichloroethyl chloroformate was developed. A key discovery that enabled the efficient and industrial-scalable process is linked to the rigorous extrusion of water in the reaction system and application of an organic catalyst such as 4-(N,N-dimethylamino)pyridine (DMAP) instead of the alkali metal bicarbonate additives. Namely, in the previously known process, the concomitant presence of bicarbonates and traces of water triggers side reaction cycles that produce and accumulate hydrochloric acid and water. The former slows down the reaction. Moreover, these cycles cause the formation of multiple carbonate and alcohol-type side products to a significant extent that provide a low-quality N-6-demethylated product. All of these shortcomings are circumvented by the application of DMAP as a catalyst and the use of a reaction medium free of water. This approach allows operation on an industrial scale (51 kg batch) with higher yields, shorter reaction times, and improved product quality.

Full text of DOI:10.1021/op500394f

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Technical Note
A DMAP Catalyzed Approach to the Industrial Scale
Preparation of N-6-Demethylated 9,10-Dihydrolysergic Acid
Methyl Ester: a Key Cabergoline and Pergolide Precursor
Zdenko Casar, and Tomaz Mesar
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/op500394f • Publication Date (Web): 31 Dec 2014
Downloaded from http://pubs.acs.org on January 1, 2015
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A DMAP Catalyzed Approach to the Industrial Scale Preparation of
N-6-Demethylated 9,10-Dihydrolysergic Acid Methyl Ester: a Key
Cabergoline and Pergolide Precursor
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Zdenko Časar,a,c* and Tomaž Mesara,b
a Lek Pharmaceuticals d.d., Sandoz Development Center Slovenia, API Development, Kolodvorska 27, 1234
Mengeš, Slovenia, Phone: +386 1 580 20 79, Fax: +386 1 568 35 17; Eꢀmail: zdenko.casar@sandoz.com
b Lek Pharmaceuticals d.d., API Production, Kolodvorska 27, 1234 Mengeš, Slovenia
c Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia
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A DMAP Catalyzed Approach to Cabergoline and Pergolide Precursor
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Abstract: A scalable new approach for the preparation of Nꢀ6ꢀdemethylated 9,10ꢀ
dihydrolysergic acid methyl ester using 2,2,2ꢀtrichloroethyl chloroformate was
developed. A key discovery that enabled efficient and industrial scalable process is
linked to the rigorous extrusion of water in the reaction system and application of an
organic catalyst such as 4ꢀdimethylaminopyridine instead of the alkali metal bicarbonate
additives. Namely, the concomitant presence of bicarbonates and traces of water
triggers, in the previously known process, the side reaction cycles, which produce and
accumulate hydrochloric acid and water. The former slows down the reaction.
Moreover, these cycles cause the formation of multiple carbonate and alcoholꢀtype side
products in significant extent that provide a low quality Nꢀ6ꢀdemethylated product. All
these shortcomings are circumvented by the application of DMAP catalyst and use of a
reaction medium free of water. This approach allows operation on the industrial scale
(51 kg batch), with higher yields, shorter reaction times and improved product quality.
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Key words: drugs, cabergoline, pergolide, heterocycles, ergoline, demethylation,
organocatalysis
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Ergot alkaloids, also known as ergolines, represent a structurally reach indole based family
of compounds with diverse pharmacological properties.1 The common structural feature of ergot
alkaloids is substituted tetracyclic ergoline ring system (Scheme 1). The most prominent
subgroup in ergoline family of compounds is constituted on naturally occurring Dꢀlysergic acid
derivatives (Scheme 1), which are produced by fungus Claviceps.2 The origin of biological
activity of ergolines is tightly linked to the tetracyclic ergoline skeleton, which resembles to those
of neurotransmitters such as dopamine, noradrenaline and serotonin.3 Moreover, structural
manipulation of functionalities attached to ergoline scaffold provided derivatives with either
agonistic or antagonistic activity.4 Two interesting and clinically used examples of this kind are
pergolide5ꢀ6 and cabergoline.7ꢀ9 Indeed, both compounds have been used in the treatment of
hyperprolactinemia10 and Parkinson’s disease.11 Although recent advances in synthetic chemistry
have enabled fully synthetic approaches to the ergoline skeleton,12 the most economically viable
synthesis of ergoline derivatives relies on biotechnological preparation of Dꢀlysergic acid amide
derivatives (e.g. ergocryptine),13 followed by subsequent functional group transformation on the
ergoline scaffold.14 A key step in these semisynthetic approaches constitutes the replacement of
naturally derived Nꢀ6 methyl group with suitable functionality. Generally, Nꢀdealkylations are
considered as challenging and capricious transformations.15ꢀ16 Although many of these literature
known Nꢀdealkylation approaches have been applied on biotechnologically derived ergot alkaloid
precursors in the synthesis pergolide6 and cabergoline,8ꢀ9 we have decided to use 2,2,2ꢀ
trichloroethyl chloroformate (2) (known as TrocꢀCl)17ꢀ18 based approach for the Nꢀdemethylation
of 9,10ꢀdihydrolysergic acid methyl ester (1) in our quest towards cabergoline and pergolide
(Scheme 1).
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Scheme 1. Synthesis of cabergoline and pergolide together with the structure of their key
precursors: ergoline skeleton, Dꢀlysergic acid amides, ergocryptine and dihydroergocryptine.
Our decision was promoted by the fact that some of the previously known approaches use
very toxic or foul smelling reagents like BrCN and alkylmercaptane salts.6d Moreover, TrocꢀCl
based Nꢀdemethylation has already been successfully applied on a kilogramme scale in the
presence of the ProtonꢀSponge® for the preparation of other active pharmaceutical ingredient:
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duloxetine.19 In addition, the starting ester (1), can be easily obtained via the efficient
semisynthetic approach involving the fermentation process, which gives ergocryptine,20 followed
by the hydrogenation to dihydroergocryptine (DHEC),21 subsequent cleavage of the peptide
residue under the basic conditions and esterification of the acid moiety with MeOH (Scheme 1).22
The original approach for the Nꢀdemethylation of 1 using 2,2,2ꢀtrichloroethyl chloroformate 2,
that provides (3) was described by Crider et al.23 on the lab scale. The subsequent removal of
Troc protection on the cyclic nitrogen of 3 was easily accomplished with Zn/AcOH to furnish (4)
as the key precursor of ergot alkaloid based drugs (Scheme 1).23
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We started our investigation24 with the evaluation of the method presented by Crider et al.23
for removal of NꢀMe moiety in 1, which is based on the reaction of 1 with 2 (6.6 equiv.) in the
presence of KHCO3 (4.9 equiv.) in absolute CH2Cl2 at reflux for 48 hours and provides,
according to the literature, 90% yield of 3 on ca. 0.4 g scale (Table 1, entry 1). Firstly we
repeated the original procedure of Crider et al. 23 on ca. 2.1 g scale (scale is defined based on the
amount of the starting 1) in two parallel experiments. To our surprise, the reaction did not
proceed according to our expectation as evidenced by only ca. 37–51% conversion of 1 in 48
hours. Moreover, after the recrystallization of the crude product from the absolute methanol only
30–35% yield of 3 was obtained with chromatographic purity above 99 area% (Table 1, entry 2,
see Supporting Information for experimental details). Based on this outcome of the initial
experiments, we thought to optimize the procedure in order to drift the reaction to completion.
Our first set of foreseen improvements of the original procedure involved a gradual addition of 2
instead of the double portionwise addition (initial one and subsequent one after 24 h of reaction
time), the use of cheaper NaHCO3 instead of KHCO3 and the application of the filtration of the
crude product over the aluminum oxide prior to the final crystallization in order to remove the
unreacted 1, potential process impurities, acidic residues and salts, which could hamper the high
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yielding crystallization of 3. Therefore, based on the above list of potential improvements 1 (5 g
scale) was reacted with 2 (6.82 equiv.), which was dosed gradually over the first 24 hours
followed by the additional 24 hours reaction time in CH2Cl2 at reflux and in the presence of
NaHCO3 (4.9 equiv.). Interestingly, ca. 84% conversion of 1 and the formation of 3 in 83%,
according to the HPLC analysis of the reaction mixture, were achieved. Subsequent filtration of
the reaction mixture over the aluminum oxide, evaporation of the CH2Cl2 and crystallization of
the residue from the absolute methanol provided 76% of 3 as a white solid (Table 1, entry 3 and
Figure 1, see Supporting Information for experimental details). Since this first set of
optimizations afforded favorable outcome, albeit the reported yield was still not achieved, we
decided to perform the first notable scale up of the reaction. In addition, we also decided to
implement further optimization steps, which could provide beneficial effect: the use of
additionally azotropically preꢀdried CH2Cl2 for the reaction, the use of additional excess of 2,
application of prolonged reaction time and the use hexane instead of methanol in the
crystallization in order to increase the yield of precipitated 3. By applying the above additional
procedure modifications 1 (600 g) was reacted with 2 (8.7 equiv., added gradually over 70 h) in
the presence of NaHCO3 (4.9 equiv.) in azotropically preꢀdried CH2Cl2 for 90 hours. The HPLC
analysis of the crude reaction mixture indicated ca. 82% conversion of 1 and formation of 3 in ca.
77%. Subsequent filtration of the reaction mixture over the aluminum oxide, evaporation of the
main part of CH2Cl2 and crystallization of the product from CH2Cl2 concentrate by addition of
hexane provided 3 in moderate 59% yield. (Table 1, entry 4 and Figure 1, see Supporting
Information for experimental details). This result indicated a negative impact of the scale up on
the reaction outcome. To verify this hypothesis we further increased the scale. For this purpose
we reacted 1 (4.6 kg) with 2 (7.4 equiv.; 27% charged initially and the rest gradually over the
reaction time) in the presence of NaHCO3 (4.9 equiv.) in dry CH2Cl2 for 92 hours, which
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afforded ca. 73% conversion of 1 according to the HPLC analysis of the crude reaction mixture.
Subsequent filtration of the mixture over the aluminum oxide followed by the removal of the
main part of the parent solvent and precipitation of the product by the addition of less expensive
heptane antisolvent (vs. hexane) provided the product 3 in moderate 56% yield (Table 1, entry 5
and Figure 1, see Supporting Information for experimental details). At this point we have realized
that the present NaHCO3 mediated reaction will be a difficult one to use on industrial scale, due
to the decreased performance observed along with the increased scale.
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Therefore, we were first stimulated to investigate the reasons for the observed unexpected
drawbacks of the Crider’s procedure. The analysis of the crude reaction mixtures with the GCꢀ
MS provided interesting insights into the side products formed in the course of the reaction
progress. Indeed, the GCꢀMS analysis enabled us to detect expected MeCl byꢀproduct and
considerable amounts of three key side products. Based on the mass spectra and their comparison
with reference spectra (NIST library) two of them were assigned to be the 2,2,2ꢀtrichloroethanol
II and the symmetric bis(2,2,2ꢀtrichloroethyl) carbonate III, while the third was presumed to be
the asymmetric methyl (2,2,2ꢀtrichloroethyl) carbonate IV based on its chromatographic
properties and mass spectrum (see Supporting Information document for the analytical details).
These observations have been additionally supported by the literature reports which highlighted
the reactivity of 2 in the protic media, where alcohol II, carbonate III and carbonate IV25 have
been reported or proposed as key degradation products of 2.17,25 Therefore, these insights have
enabled us to construct the plausible reaction pathways24 for the reaction of 1 with 2 in the
presence of KHCO3 (Scheme 2). Compound 3 is produced via 3’ and release of MeCl as the byꢀ
product of the reaction, when 2 reacts with 1. However, if water is present in the reaction mixture
even at low levels it could react with 2 to produce HCl and 2,2,2ꢀtrichloroethyl hydrogen
carbonate I. The released HCl would immediately react with KHCO3, which would result in the
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formation of additional H2O, CO2 and KCl. The additionally released water would react again
with 2 via the release of HCl and 2,2,2ꢀtrichloroethyl hydrogen carbonate I, followed by the
reaction with KHCO3 to form a selfꢀsustainable H2O and HCl generating cycle (colored blue in
Scheme 2). The carbonate I as the key product of the first cycle is too unstable and would
undergo the decomposition to the alcohol II24,25 and release of additional CO2 molecule. The
formed alcohol II would react with 2, that is present in the mixture in high excess, which would
result in the formation of the symmetric carbonate III and the release of additional molecule of
HCl (second mole of HCl per mole of starting H2O and two moles of 2). This pathway would
close an additional linked (connected) cycle (colored light red in Scheme 2), which is responsible
for the generation of the alcohol II and the symmetric carbonate III. Moreover, the HCl released
in the linked cycle would enter the first HCl and H2O forming cycle as the initial cycle amplifier.
The two operating linked cycles would be responsible for the excessive generation of HCl and
H2O and side products II and III, which are amplified through every operated cycle. The huge
access of the released HCl would eventually stop the primary Nꢀdemethylation reaction via
protonation of the cyclic nitrogen in 2, which is indeed observed experimentally. The additional
pathway that is probably operational in the system is linked to the formation of the carbonate
IV.25 The later might be formed via the reaction of 2 with methanol, where the latter might be
produced from released MeCl and water generated in the reaction system. In such pathway the
additional two molecules of HCl would be released giving the additional amplification
momentum to the HCl and H2O generating cycle.
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Scheme 2. Reaction pathways in the reaction between 1 and 2,2,2ꢀtrichloroethyl chloroformate 2
in the presence of KHCO3.24ꢀ25
Based on the observed drawbacks of bicarbonate additives in the reaction between 1 and 2,
we have considered other bases that could act favorably in the studied transformation. Although a
ProtonꢀSponge® has been used in combination with 2,2,2ꢀtrichloroethyl chloroformate 2, for the
Nꢀdemethylation in the preparation of an active pharmaceutical ingredient (e.g. duloxetine) on
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kilogram scale,19 there are notable drawbacks of proton sponge derivatives. Namely, they are
usually used on above catalytic amount or even in several fold excesses, which makes such
processes less economical feasible. Moreover, the workup of reactions using notable excess of
proton sponge derivatives can be challenging as well.26 Therefore, we have decided to turn our
attention to the possible catalytic approaches. We thought that for this reason 4ꢀ
dimethylaminopyridine (DMAP), which already proved to be a useful nucleophilic catalyst for a
variety of reactions, might be a good alternative.27ꢀ28 For this reason we performed, in parallel,
two sets of reactions. In the first set KHCO3 mediated reaction and DMAP catalyzed reaction
between 1 and 2 were benchmarked against each other (see Supporting Information for
experimental details). In the second set the KHCO3 mediated reaction and DMAP catalyzed
reaction between 1 and 2 were compared after the additional pretreatment of the reactant solution
was performed prior to the addition of 1 and additive or catalyst (quench of water in the solvent
with 2 and elimination of released HCl by nitrogen purging of the solution, see Supporting
Information for experimental details). In both cases the results were striking. Indeed, in the first
set of reactions the DMAP catalyzed method significantly outperformed the KHCO3 mediated
reaction. The most notable advantages were observed in the yield of isolated product 3 and its
assay. Indeed, the DMAP catalyzed reaction provided ca. 11% higher yield of 3 compared to the
KHCO3 mediated reaction (69.5% vs. 58.5% yield). Moreover, a huge difference between
KHCO3 mediated reaction and DMAP catalyzed reaction was also observed when the assay was
determined based on the external standard with the HPLC. While the assay of product 3 obtained
with KHCO3 mediated reaction was only 84%, the product obtained with DMAP catalyzed
reaction possessed an assay of 101%. Furthermore, when samples of isolated 3 were analyzed
with GCꢀMS, a notable level of alcohol II and carbonates III and IV were present in the product
obtained with KHCO3 mediated reaction (see Supporting Information for analytical data). These
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results explain the lower assay of products 3 obtained via the KHCO3 mediated reaction. In the
second set of reactions the initial trace water was quenched with 2 and released hydrochloric acid
was eliminated by nitrogen purging of the obtained solution prior to the addition of 1 and additive
(KHCO3) or catalyst (DMAP). In this case the isolated yields of 3 were notably higher (98.9–
100%) than in the previous set of reactions (see Supporting Information for analytical data).
However, the HPLC analysis of the precipitated product indicated that the KHCO3 mediated
reaction provided product 3, which contained significant amount of unreacted 1 (ca. 30 area%),
while the product obtained via the DMAP catalyzed process contained 98.3 area% of 3 and only
1.3 area% of 1. Consequently, the assay determined via HPLC method with external standard
indicated that 3 obtained via metal bicarbonate mediated reaction had an assay of 73.8%, while
the assay of 3 obtained from the DMAP catalyzed process was 97.4%. These promising results
directed us to perform the scale up of DMAP catalyzed reaction. Progression from the lab scale to
the pilot scale, where the reaction was conducted with 4.4 kg of the starting 1 in the presence of
4.7 eq. of 2 and 5 mol% of DMAP, proceeded smoothly and high 86.9% conversion to 3
(measured as a HPLC area%) was reached already in 22 h while the starting 1 was present in
11.7%. After the filtration of the reaction mixture over the alumina followed by the precipitation
of the product with heptane from the concentrated CH2Cl2 solution, 3 was obtained as in 76%
yield, and 99.7% chromatographic purity and nearly 100% assay. This encouraging result
directed us to further increase the scale to full production level, where 51 kg of starting 1 in the
presence of 4.8 eq. of 2 and 5 mol% of DMAP was reacted. In order to test, if even higher
conversion could be obtained, slightly higher amount of 2 was used (0.1 equiv. compared to the
pilot scale) and also the reaction time was prolonged from 22 to 30 hours compared to the pilot
scale reaction. Gratifyingly, we have observed that excellent 94% conversion to 3 was obtained
along with 5.9% of starting 1 remaining in the mixture. This high purity crude reaction mixture
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allowed us to isolate the desired product 3, after the filtration over the alumina, concentration of
the CH2Cl2 solution and addition of the heptane as antisolvent, in excellent 94% yield with
excellent purity (100 area%) and nearly 100% assay.
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The advantages of the organocatalytic process over the standard bicarbonate mediated
process are summarized in Table 1 and graphically in Figure 1, where kinetics of discussed
reactions are plotted against each other. The Table 1 presents comparison of yields, reaction
times and reagent stoichiometry (molar ratio between 1 and 2). From Table 1 and Figure 1
favorable effects on the process are clearly visible, especially when using organocatalysis over
the standard metal bicarbonate mediated process. The process depicted in Table 1, entry 7
provides the highest conversion of 1 to 3 and the highest yield of 3 in short reaction time.
Table 1. Comparison of KHCO3 and NaHCO3 mediated reaction with DMAP catalyzed reaction
.
Yield [%]†
Entry Type and scale of reaction
additive
KHCO3
Reaction time
[h]
Molar ratio
2/1
1
2
3
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5
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literature data,23 lab scale (0.425 g)
repeated literature data, lab scale (2.13 g)
optimized literature, lab scale (5 g)
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90
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90
6.6 : 1
6.6 : 1
6.8 : 1
8.7 : 1
7.4 : 1
4.7 : 1
4.8 : 1
KHCO3
30ꢀ35
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NaHCO3
optimized literature, kilo lab scale (600 g) NaHCO3
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optimized literature, pilot scale (4.6 kg)
organocatalysis, pilot scale (4.4 kg)
NaHCO3
DMAP
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organocatalysis, industrial scale (51.0 kg) DMAP
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†
In all the cases the reactions were run at reflux of CH2Cl2. Values refer to product obtained after
precipitation from the corresponding solvent (see experimental section and Supporting Information
document).
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Figure 1. Comparison of the reaction kinetics for DMAP catalyzed and NaHCO3 mediated reactions:
higher yield and shorter reaction time is achieved for the DMAP catalyzed reaction with the increasing
scale while the opposite trend is observed in the case of NaHCO3.
In summary, we presented a successful development and scaleꢀup of Nꢀ6 demethylation
reaction of 9,10ꢀdihydrolysergic acid methyl ester 1 for the preparation of strategic common
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precursors 3 and 4 in the synthesis of pergolide and cabergoline. The key success factor for the
effective tackling of issues associated with the literature known method,23 was identification of
“parasitic reactions” involving 2,2,2ꢀtrichloroethyl chloroformate 2, which takes place when the
reaction is conducted in industrial grade dry solvent in the presence of a base such as alkali metal
bicarbonates. These side reactions form selfꢀsustainable HCl and water generating cycles that
accumulate tedious to remove alcohol and carbonateꢀtype side products. These impurities cause
lower purity and assay of the desired reaction product. Furthermore, the replacement of
stoichiometric quantities of previously used alkali metal bicarbonates23 with 5 mol% of 4ꢀ(N,Nꢀ
dimethylamino)pyridine (DMAP) as an effective nucleophilic base catalyst significantly reduced
salt waste streams and provided a dramatic improvement effect on overall reaction outcome.24,29
Indeed, the beneficial effect of scaleꢀup on conversion was observed for the DMAP catalyzed
reaction, whereas the opposite trend is noted for the alkali metal bicarbonate mediated reaction.
Notably, the DMAP catalyzed reaction could be nearly completed in less than 24 hours giving
94% isolated yield on industrial scale batch (51 kg), whereas alkali metal bicarbonate mediated
reaction allowed only 56% yield even on one magnitude of order lower scale (4.6 kg) in
significantly longer reaction time (92 h). Due to these facts, we trust that our results will promote
the application of DMAP type organocatalysis in pharmaceutical industry area.
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Experimental
General considerations
All reagents and solvents were used as purchased from commercial sources. The starting material
1 was prepared inꢀhouse on industrial scale according to the known literature synthetic strategies
starting from fermentatively derived ergocryptine,20 followed by the hydrogenation,21 amide bond
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hydrolysis and esterification.22,29 NMR spectra were recorded at 298 K on a Bruker Avance III
500 spectrometer operating at 500 MHz (1H), 125 MHz (13C) respectively. Proton and carbon
spectra were referenced to TMS as internal standard or residual solvent signals. Chemical shifts
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are given on the
indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), sep (septet), m (multiplet), or
br (broadened). ighꢀresolution mass spectra were obtained with Agilent 6224 Accurate Mass
δ scale (ppm). Coupling constants (J) are given in Hz. Multiplicities are
H
TOF LC/MS system. Infrared spectra were recorded on a Thermo Nicolet Nexus spectrometer
using samples in potassium bromide disks. Melting points were determined on Mettler Toledo
DSC apparatus 822e (heating rate 10 °C/min). For flash chromatography, aluminum oxide
particle size 0.05–0.15mm, pH 9.5 was used. HPLC analyses were performed on a Waters 2487
instrument with dual λ absorbance detector and Synergi Polar–RP3 8CA 150 × 4.6 mm column
was used. HPLC conditions: 30 °C, 1.0 mL/min, 280 nm, aqueous pH 2.5 buffer (NaH2PO4):
acetonitrile = 90:10 → 10:90. Rt compound 1 = ca. 9.8 min. Rt compound 3 = ca. 23.4 min.
Preparation of (3) by application of DMAP catalyst on pilot scale (4.4 kg). A 250 L reactor
containing a 186 kg of dry dichlorometane was charged with 15.4 kg (72.96 mol) 2,2,2
–
trichloroethyl chloroformate 2 at 20 ± 5 °C. The mixture was heated to reflux and refluxed for at
least 3 hours. After, the mixture was cooled to 20 ± 5 °C. The reactor was purged with nitrogen
for at least 15 min. and charged with 88 g (0.72 mmol) of DMAP at 20 ± 5 °C. The obtained
mixture was then stirred at 20 ± 5 °C for at least 1 hour. The reactor was purged with nitrogen for
at least 15 min. and charged with 4.4 kg (15.47 mol) of 1 at 20 ± 5 °C. The obtained mixture was
then heated to reflux and refluxed for 22 hours. After the reaction mixture was cooled to 10 ± 5
°C and filtered through a pad of alumina. Fractions containing a product were collected,
concentrated and cooled 10 ± 5 °C. Then heptane was added to the concentrated solution and the
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precipitated product was collected by centrifugation. After drying, 5.25 kg (76%) of 3 was
obtained with chromatographic purity of 99.7area%. The assay of 3 was 100% determined by
HPLC according to the external standard.
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Industrial process for the preparation of (3) using DMAP. An industrial reactor containing a
1220 kg of dry dichloromethane was charged with 182.7 kg (862.36 mol) of 2,2,2–trichloroethyl
chloroformate 2 at 20 ± 5 °C. The mixture was heated to reflux and refluxed for at least 3 hours.
After, the mixture was cooled to 20 ± 5 °C. The reactor was charged with 1022 g of DMAP (8.37
mol) at 20 ± 5 °C. The obtained mixture was then stirred at 20 ± 5 °C for at least 1 hour. Then the
reactor was charged with 51.0 kg (179.36 mol) of 1 at 20 ± 5 °C dissolved in dry
dichloromethane (720 kg). The obtained mixture was then heated to reflux and refluxed for 30
hours. After the reaction mixture was cooled to 10 ± 5 °C and filtered through a pad of alumina.
Fractions containing the product 3 were collected, concentrated and cooled 0 ± 5 °C. Then
heptane was added to the concentrated solution and the precipitated product was filtered on filterꢀ
dryer. After drying, 75.1 kg (94%) of 3 was obtained with chromatographic purity of 100area%.
The assay of 3 was nearly 100% determined by HPLC according to the external standard. M.p. =
1
203.8 °C (DSC onset), 204.7 °C (DCS peak) (lit23 208ꢀ210). H NMR (DMSOꢀd6): δ 10.72 (d, J
= 1.5 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 7.07–7.02 (m, 1H), 7.01 (bs, 1H), 6.82 (d, J = 7.1 Hz,
1H), 4.86 (d, J = 1.5 Hz, 2H), 4.05 (dd, J1 = 14.1, J2 = 2.9 Hz, 1H), 3.79 (dd, J1 = 14.1, J2 = 6.2
Hz, 1H), 3.70–3.66 (m, 1H), 3.65 (s, 3H), 3.33–3.27 (m, 2H), 3.08–3.03 (m, 2H), 2.82–2.77 (m,
1H), 1.72–1.65 (m, 1H). 13C NMR (DMSOꢀd6): δ 174.7; 154.0, 133.8, 132.3, 126.4, 122.5, 119.3,
112.5, 110.6, 109.8, 96.4, 74.6, 60.5, 52.4, 42.3, 39.7, 36.7, 27.5, 25.7. IR (KBr) ν 1742, 1720,
1438, 1422, 1252, 1172, 1130, 1090, 1068, 1047, 1030, 875, 842, 814, 788, 757, 719, 668, 585
cmꢀ1. HRMS (ESI+) calcd for C19H19Cl3N2O4 ([M + H]+): 445.0483; found: 445.0482. This is a
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known compound with spectroscopic and physical properties in accordance with those reported
in the literature.23,29
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Author Information
Corresponding Author
*Eꢀmail: zdenko.casar@sandoz.com
Author Contributions
Author ZČ contributed 90% and author TM contributed 10% of the effort to this manuscript.
Notes
The authors declare no competing financial interest.
Acknowledgements
Authors gratefully acknowledge Lek Pharmaceuticals d.d. for the support of this work. Special gratitude
goes to Mr. D. Orkič for the extensive GC–MS analytics. Mrs. J. Anželj (dipl. ing.) is kindly
acknowledged for her support in synthetic lab experiments. Mrs. L. Kolenc, Mr. S. Borišek, Mr. M.
Borišek, and Mr. M. Uštar (MSc) are acknowledged for the assistance in some analytical work. Dr. M.
Črnugelj is acknowledged for the acquisition of NMR spectra as well as Dr. D. Urankar and Prof. J.
Košmrlj (University of Ljubljana) for HRMS analysis. Last but not least, the crew of API Development
pilot plant is gratefully acknowledged for the production of all the technical pilot scale batches described
in this work. We also thank Mr. T. Marko (BsChE), for his contribution in technical design of equipment
and fruitful collaboration during pilot plant campaigns. As well, B. Borin (BsChE) and Dr. B. Kralj are
acknowledged for the contribution in the manufacture of industrial scale batches.
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Associated Content
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Supporting Information.
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Copies of H NMR, C NMR, DEPT 135, IR spectra and DSC thermogram of 3 as well as the
comparative experimental procedures leading to the present synthetic method. This information is
available free of charge via the Internet at http://pubs.acs.org/.
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[21] For the synthesis of dihydroergocryptine from ergocryptine, see: Stoll, A.; Hofmann, A.
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[22] For the synthesis of (1) via two step hydrolysis/esterification strategy starting from
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[23] Crider, M. A.; Grubb, R.; Bachmann, K. A.; Rawat, A. K. J. Pharm. Sci. 1981, 70,
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[24] The work presented in this article is based on our patent application: Časar, Z.; Mesar,
T. PCT Int. Appl. WO 2009133097 A1, 2009; Chem. Abstr. 2009, 151, 528967.
[25] After the publication of our invention, cited in the ref. 24 of the present manuscript,
where we have already presented the plausible degradation reaction pathways of 2
which generate discussed side products II, III and IV, a mechanistic study on solvolysis
of 2,2,2ꢀtrichloroethyl chloroformate in various solvents was reported. This study
additionally confirmed our initial hypothesis on the reaction pathways involving 2,2,2ꢀ
trichloroethyl chloroformate 2 in the presence of protic solvents. It also presents an
additional degradation pathway via the formation of Cl3CCH2Cl from 2: Koh, H. J.;
Kang, S. J. Bull. Korean Chem. Soc. 2012, 33, 1729–1733 and references cited therein.
[26] Schneider, E. M.; Raso, R. A.; Hofer, C. J.; Zeltner, M.; Stettler, R. D.; Hess, S. C.;
Grass, R. N.; Stark, W. J. J. Org. Chem. 2014, 79, 10908–10915 and references cited
therein.
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[28] For selected articles on DMAP and analogues in catalysis, see: (a) Litvinenko, L. M.;
Kirichenko, A. I.; Dokl. Akad. Nauk SSSR Ser. Khim. 1967, 176, 97–100. (b) Zanka, A.;
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[29] Our invention cited in the reference 24 of the manuscript was also used by other authors
on the laboratory scale for the preparation of European pharmacopoeial impurities A, B,
C, and D of cabergoline: Wagger, J.; Požes, A.; Požgan, F. RSC Adv. 2013, 3, 23146–
23156.
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