Redesign of a Grignard-Based Active Pharmaceutical Ingredient (API) Batch Synthesis to a Flow Process for the Preparation of Melitracen HCl

Article abstract of DOI:10.1021/acs.oprd.7b00368

A Grignard-based batch process, for the preparation of Melitracen HCl, has been redesigned to fit a continuous reactor system. The Grignard addition is carried out at room temperature, with subsequent hydrolysis of the magnesium alkoxide intermediate followed by dehydration of the resulting alcohol. The product undergoes further workup by simple gravimetric phase separation and then crystallization with 2 M HCl in diethyl ether to afford pure Melitracen HCl. All steps in the laboratory setup were concatenated, and the setup was proven capable of producing a significant portion of the commercial quantities of Melitracen HCl. The flow setup profits from a reduced footprint, lower energy consumption, fewer synthetic steps, and reduced raw material usage compared to the batch process.

Full text of DOI:10.1021/acs.oprd.7b00368

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Full Paper
Redesign of a Grignard-Based API Batch Synthesis to
a Flow Process for the Preparation of Melitracen HCl
Michael J. Pedersen, Tommy Skovby, Michael J. Mealy, Kim Dam-Johansen, and Søren Kiil
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00368 • Publication Date (Web): 04 Jan 2018
Downloaded from http://pubs.acs.org on January 4, 2018
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Redesign of a GrignardꢀBased API Batch Synthesis
to a Flow Process for the Preparation of Melitracen
HCl
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Michael J. Pedersen,†,‡ Tommy Skovby,† Michael J. Mealy,† Kim Dam-Johansen,‡ Søren Kiil*,‡
† H. Lundbeck A/S, Oddenvej 182, 4500 Nykøbing Sjælland, Denmark
‡ Department of Chemical and Biochemical Engineering, Technical University of Denmark,
DTU, Building 229, 2800 Kgs. Lyngby, Denmark
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Synopsis
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HCl(aq)
P3
AcOH (aq)
P4
3
NH (aq)
P5
DMPC-MgCl P2
10,10-DMA P1
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C1
C2
C3
C4
IR
BPR
T1
T2
T3
P6
T4
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HCl 2M in DEE P7
Decanter
Aq waste
Melitracen
HCl
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Abstract
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A Grignardꢀbased batch process, for the preparation of Melitracen HCl, has been redesigned to
fit a continuous reactor system. The Grignard addition is carried out at room temperature, with
subsequent hydrolysis of the magnesium alkoxide intermediate followed by dehydration of the
resulting alcohol. The product is further workedꢀup by simple gravimetric phase separation and
then crystallized with 2 M HCl in diethyl ether to afford pure Melitracen HCl. All steps in the
laboratory setup were concatenated and the setup was proven capable of producing a significant
portion of the commercial quantities of Melitracen HCl. The flow setup profits from a reduced
footprint, lower energy consumption, fewer synthetic steps and reduced raw material usage
compared to the batch process.
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Keywords: Grignard alkylation, Flow chemistry, API synthesis, liquid phase separation.
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Introduction
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The efficiency of the pharmaceutical industry has been a widely discussed topic throughout the
past decade. The debate has been broad, ranging from early target drug development to the actual
production and distribution of pharmaceuticals.1–6 Expiring patents and empty pipelines have
forced pharmaceutical companies to look for alternative methods to remain competitive against
generic manufacturers.7–9 Furthermore, the industry has one of the highest solventꢀtoꢀcarbon
ratios,10 which in combination with the fact that most of these solvents have high environmental
impacts has given the industry a somewhat damaged reputation.5,10–13 In addition, the authorities
have steadily increased the tightening of legislative requirements for pharmaceutical
manufacturing, in both development and production.3,5
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With respect to the production of active pharmaceutical ingredients (APIs), the focus has
especially been on batch methods and their insufficiency, especially their mass and heat transfer
properties.14,15 As early as the 1970s, Popov16 suggested continuous manufacturing as a method
for improving the efficiency of pharmaceutical production. However, it was not until the last
decade that progress was seen. The establishment of the pharmaceutical round table and the
increased interest from academia and industry have been driving the transformation
forwards.4,5,17–20 The authorities have since 2002 acknowledged new production methods and
strategies within manufacturing. Process analytical technology (PAT) approaches and
QualityꢀbyꢀDesign (QbD) concepts have been important factors in the acceptance of continuous
manufacturing by the authorities.9,21,22
Earlier publications concerning the new paradigm of pharmaceutical manufacturing often
focused on single synthesis steps and unit operations, often with the use of microreactor
technology.23,24 Later trends have changed the focus towards multiple synthesis steps,
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pharmacyꢀonꢀdemand and endꢀtoꢀend manufacturing.17–19,25 As the trend has moved from single
step to endꢀtoꢀend manufacturing,18 the previous outꢀscaling concept23 of microreactors has also
been replaced by miniꢀscale flow systems.18,20,26–28 The scaleꢀup of a continuous setup needed to
meet fullꢀscale requirements is often minor; hence the benefits such as mass and heat transfer are
almost comparable to microreactor technology.15
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Reactions having multiple phases still pose a significant challenge within flow chemistry.29–31
Flow reactors are known for being poor at handling solid material due to clogging issues, with
some exceptions such as packed bed reactors with fixed catalytic material. Breakthroughs for
flow reactors that can handle solid reactants or products have within recent years been
demonstrated, such as the desulfurization of substituted thioimidazoles by Baxendal et al.32, the
powder dosing unit for a CSTR demonstrated by Hu et al.33 and precipitation in flow
demonstrated by Baxendal et al.34
The pharmaceutical industry is notorious for their usage of solid compounds, either as
reactants, intermediates or APIs.29,31 Low solubility is often a huge obstacle for applying the
chemistry to a flow setup, unless alternative methods are applied.2,31 Solubility is one of the key
parameters when designing a reactor setup and an instructive discussion may be found in
Pedersen et al.20 In cases of high solubility, the simple use of a plug flow reactor (PFR) can be
applied, often with great success and larger throughput.28,35 The challenging part then becomes
the purification of the product from impurities and unreacted reactants, as well as the final
isolation of the product. Many old batch processes utilize the benefits of precipitation as a
purification step, hence altering an old batch process to fit a flow setup requires new ways to
overcome these challenges.2,20,29
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Grignard reactions serve as a commonly used method for the formation of carbonꢀcarbon
bonds in the development of APIs36,37. The exothermic behavior of the Grignard reaction makes
it ideal for continuous production. Several demonstrations of Grignard reactions in flow have
been done within the last decade: Kopach et al.38,39 demonstrated the use of a CSTR technology;
Pedersen et. al20,26,40 demonstrated the use of a heterogeneous slurry filter reactor; Mateos et al.41
studied the formation of ketone by nucleophilic Grignard addition to nitril groups by use of flow
methods; Lonza42–44 has demonstrated the use of micro reactor technology.
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Chemistry
As illustrated in Scheme 1, four synthetic steps are involved in the manufacturing of
Melitracen HCl (6). The four steps are a classic Grignard addition to a ketone, a hydrolysis of a
magnesium alkoxide, a dehydration of an alcohol and a salt precipitation to isolate the API. The
Grignard addition is between 10,10ꢀdimethylanthrone (10,10ꢀDMA (1)) and
3ꢀ(N,Nꢀdimethylamino)propylmagnesium chloride (DMPCꢀMgCl (2)), resulting in formation of
the magnesium alkoxide 3. The magnesium alkoxide 3 is then hydrolyzed to the alcohol 4 and
dehydrated to form product 5. The last step is a crystallization of the API as a salt, where HCl is
added to obtain the Melitracen HCl (6).
Scheme 1: Syntheses of magnesium alkoxide 3, alcohol 4 and dehydrated product 5 in the
manufacturing process of Melitracen HCl 6, from ketone 1 and Grignard reagent 2.
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Current Batch Synthesis
The current batch synthesis involves individual synthetic steps, as illustrated in Figure 1.
DMPCꢀMgCl 2 is made inꢀhouse before it is used, due to its limited storage shelf life, in a
tolueneꢀTHF solvent mixture. THF is present in trace amounts in order to stabilize the
magnesium in the Grignard reagents.45 A solution of 10,10ꢀDMA 1 is prepared in toluene and is
slowly transferred to the DMPCꢀMgCl 2, maintaining a temperature of 50°C. DMPCꢀMgCl 2 is
used in an equivalence of 1.6 compared to 10,10ꢀDMA 1. The formed magnesium alkoxide 3 is
hydrolyzed with water and acetic acid (80%). The aqueous phase is discarded and concentrated
hydrochloric acid (37%) is used to dehydrate alcohol 4 to form dehydrated product 5. Toluene is
replaced with ethanol by a solvent swap. Crystallization of the dehydrated product 5 from the
ethanol phase is done with HCl gas to obtain the final Melitracen HCl (6), which is subsequently
isolated by filtration.
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Figure 1: The operational steps involved in the current batch method and the simplification
achieved by the flow setup.
Investigational Strategy
The API manufacturing strategy at H. Lundbeck A/S is focused on continuous production.
Melitracen HCl synthesis currently occupies significant production facilities and is produced by
routine batch synthesis procedures. The process shows potential for being redesigned to fit a
continuous reactor setup, with potential for significant simplification of the operation and the
synthetic route. This article describes the laboratory work for redesigning the process to fit a
continuous reactor setup for the Grignard addition to the final Melitracen HCl crystallization.
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Experimental Section
Screening Experiments
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The routine batch synthesis for production of Melitracen HCl 6 was considered suitable for
redesign into a flow process, as most of the synthetic steps are categorized as fast reactions.31
The current batch methods could possibly be transferred directly into a flow setup, providing the
common benefits achieved when changing from batch to continuous processing. However,
additional savings could potentially be achieved with the flow setup if simplifications of aspects
such as the solvent choice and synthetic steps were possible. Classic batch screening experiments
were conducted to assist in the decision on and design of a flow setup and, based on these
experiments, the flow setup decided on was to be experimentally verified afterwards.
Solubility of Reactants and Products in Solvents
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The first consideration in the process for redesigning Melitracen HCl 6 synthesis is the
solubility of reactants, intermediates and products. Solubility is one of the key parameters when
designing a reactor setup. The primary focus was on the Grignard addition step, where reactants
10,10ꢀDMA 1, DMPCꢀMgCl 2 and magnesium alkoxide product 3 are of interest. DMPCꢀMgCl
2 already has a high solubility and was not tested further. 10,10ꢀDMA 1 is a solid starting
material and needs to be dissolved before it can react with DMPCꢀMgCl 2. The solubility of
10,10ꢀDMA 1 should therefore be tested in potential solvents and at different temperatures.
Magnesium alkoxide 3 is not easily isolated, as the magnesium halide part easily reacts with
water and moisture. Instead of determining the exact solubility of magnesium alkoxide 3, a
qualitative first estimate of its capability to stay in solution could be sufficient. The requirement
is, of course, that the concentration of magnesium alkoxide 3 in the reaction mixture is
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representative of the concentrations of the 10,10ꢀDMA 1 and DMPCꢀMgCl 2 intended for the
synthesis. The later synthetic steps should be tested accordingly for solubility where necessary,
since low solubility in these steps could require a lower concentration of 10,10ꢀDMA 1 and
DMPꢀMgCl 2 to have a fully operational flow setup from start to end of the synthesis.
The solubility experiments on 10,10ꢀDMA 1 focused on three solvents to be verified: toluene,
tetrahydrofuran (THF) and 2ꢀmethyltetrahydrofuran (MeTHF), all of which are suitable
candidates for later fullꢀscale production. The solubility temperature was tested up to 20°C,
which is to be considered the high limit due to ambient temperatures if no heat tracing should be
applied to pumps and pipes. Figure 2 shows the solubility of 10,10ꢀDMA 1 in the three solvents,
where THF shows a significantly higher solubility than toluene or MeTHF.
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3.0
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Temperature (°C)
Figure 2: The solubility of 10,10ꢀDMA 1 in toluene (ꢀ), THF (ꢁ) and MeTHF (ꢀ). The
10,10ꢀDMA 1 has high solubility even at low temperatures in the tested solvents. The solubility
in THF is significantly higher compared to MeTHF and Toluene (approximately 100 g/L more
10,10ꢀDMA 1).
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The significantly higher solubility of 10,10ꢀDMA 1 in THF makes it obvious to use THF. If
toluene were to be used as in the batch process, trace amounts of ether would still be needed to
stabilize the magnesium in DMPCꢀMgCl 2.
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The concentration of 10,10ꢀDMA 1 in THF was set to the lower side of 20°C (1.8 mol/L, 400
g/L) to minimize the risk of precipitation while operating a flow setup. The DMPCꢀMgCl 2 was
available at approximately 1.5 M concentration in THF from the production and it was decided
to proceed with this concentration. A couple of quick qualitative batch experiments were carried
out to verify whether the magnesium alkoxide 3 could remain soluble in the reaction mixture, as
it was not possible to isolate the unstable magnesium alkoxide 3 for a solubility study. These
experiments came out positive for the desired concentrations of 10,10ꢀDMA 1 and DMPCꢀMgCl
2 and no further testing of the solubility of magnesium alkoxide 3 was found necessary.
Phase Separation: Organic Phase and Aqueous Waste
A batch experiment, representing the expected concentration for the flow setup, was used to
verify the potential for phase separation of THF from the aqueous phase. The DMPCꢀMgCl 2
was slowly added in excess amounts with a dripping funnel to a roundꢀbottom flask of the
10,10ꢀDMA 1 solution. The mixture was afterwards hydrolyzed with water and acetic acid
(80%). The addition of the acid caused the pH of the mixture to become slightly acidic (pH ∼6)
and an oneꢀphase mixture was achieved. The pH was adjusted with aqueous ammonia (25%) and
at pH 8 a twoꢀphase mixture appeared. Alcohol 4 was distributed with 63% in the organic phase
and 37% in the aqueous, according to HPLC assay. Adjusting the pH in the aqueous phase to 10
with additional aqueous ammonia (25%) resulted in an additional organic phase, with less than
1% alcohol 4 left in the aqueous phase.
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Alcohol 4 in the organic phase was then dehydrated with hydrochloric acid (37%), followed by
adjustment of the pH to 10 with aqueous ammonia (25%). Adjusting the pH to 10 allowed a
phase separation with more than 99% of the product in the organic phase and with a ∼99% purity
of the dehydrated product 5. During the hydrolysis and dehydration, a minor precipitation of
solid material was formed that easily dissolved as the reaction progressed and should therefore
not be a major concern for a flow setup.
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At pH ≥ 10 the tertiary amine is completely deprotonated, causing the products 4 and 5 to
become almost insoluble in water, thereby achieving excellent separation. At pH ≤ 10 the tertiary
amine becomes protonated and is soluble both in the aqueous and organic phase. If a clean phase
separation had not been possible, changing the synthesis solvent to MeTHF could have
simplified the workup of the products 4 or 5 from the aqueous phase, as MeTHF is not miscible
with water.
One-Step Hydrolysis and Dehydration
The ability to phase separate both the alcohol 4 and the dehydrated product 5 in THF enabled a
simplification of the targeted flow method. Ideally, hydrolysis and dehydration should be
possible in one step, hence saving a phase separation and combining two synthetic steps into one.
Screening for a potential acid for the oneꢀstep hydrolysis and dehydration was done, focusing on
acetic acid and hydrochloric acid, either separately or in combination. Table 1 shows the results
of the product formation based on the different acid systems.
Table 1: Screening of different acids for direct hydrolysis and dehydration of the magnesium
alkoxide 3 to the dehydrated product 5.
Acid Solution
HCl 37% (aq.)
Product (%)
Phase Separation (%)
>99
Dehydrated 5 (100%)
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AcOH 80% (aq.)
Alcohol 4 (100%)
HCl 37% (aq.)/AcOH 80% (aq.) (1:1) Dehydrated 5 (90%)
Alcohol 4 (10%)
>99
>99
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As seen in Table 1, only hydrochloric acid was able to hydrolyze and dehydrate the
magnesium alkoxide mixture in one step. The experiment with hydrochloric acid resulted in
significant heat development and an immediate precipitation of solids that potentially could be
critical, even though it dissolved within a few minutes. An additional set of screening
experiments was done to verify the potential of a lower concentration of hydrochloric acid.
These experiments were carried out to verify whether the immediate precipitation of solid could
be avoided and whether the energy released from the hydrolysis and dehydration could be
distributed, as both steps are exothermic. Equal volumes of hydrochloric acid with different
concentrations (1, 3, 6, 9 and 12 M) were used. For the concentrations lower than 6 M, it was not
possible to achieve full dehydration at ambient temperature. For the concentrations equal to 6 M
and higher, full dehydration was obtained, but all concentrations resulted in precipitation of a
white solid that dissolved after few minutes of standing. From a production and environmental
perspective, the more concentrated hydrochloric acid is the optimal choice; less aqueous waste is
generated if the acid used is stoichiometric. Given the fact that precipitation could not be avoided
and the production perspective, it was decided to proceed with 12 M hydrochloric acid.
Precipitation of Melitracen HCl from THF
The dehydrated product 5 was crystallized as the final HCl salt in the THF in a batch
experiment, in order to remove a solvent swap to ethanol. The crystallization was carried out
with 2 M HCl in Et2O, as this was considered more suited for a later flow process and more
easily implemented in the laboratory setup. An equivalence of 1.1 HCl was used and the
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requirement was an achievement of pH<2. The mixture was kept stirred during the crystallization
and carried out at ambient temperature. After 10 minutes, fine white solids started to form,
followed by a massive precipitation of Melitracen HCl 6. The Melitracen HCl 6 was filtered with
a Büchner funnel and washed with THF. The isolated yield was 80% and within the
specifications for the inꢀhouse analysis methods used in the routine production (CHN, TGA,
UVꢀvis, HPLC, melting point). Figure 3 is a microscope picture of the isolated Melitracen HCl 6.
For fullꢀscale production, the HCl gas would still be more desirable for the crystallization and the
2 M HCl in Et2O merely serves as a proof of concept for the laboratory flow setup.
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Figure 3: Microscope picture of the isolated Melitracen HCl 6 from the THF solution.
Flow Process
The initial batch screening experiments all indicated that the chemistry should be run in PFRs.
This decision is based on several parameters from the screening experiments. In particular, the
high solubility of the reactants and products makes the synthesis ideal for PFRs. Additionally, all
of the synthesis steps are categorized as fast (full conversion within minutes) and hence small
reactor volumes can be used. The final setup is illustrated in Figure 4 as a flow sheet. All tubing
was 1/8” OD and 1/16” ID and made from PTFE; the Tꢀmixer was of PEEK material ID 0.04”.
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All synthetic steps were performed at ambient temperature, with no active cooling or heating. If
the reactor system was to be scaled significantly, consideration of active cooling and heating
should be taken into account due to potential safety and control related issues. Every step, except
for the addition of acetic acid and the decanter phase separation, is exothermic. The decanter was
a 100 mL glass bottle, fitted for the purpose with an inꢀhouseꢀmade PTFE lid. After the Grignard
addition (T1,C1) of DMPCꢀMgCl 2 to 10,10ꢀDMA 1, a flow IR 10 µL head from Mettler Toledo
was applied for inꢀline monitoring of the conversion and reaction. After the acetic acid addition
(T3,C3), a 100 psi back pressure regulator (BPR) was applied to avoid boiling of the THF due to
the hydrolysis and dehydration taking place at the HCl addition (T2,C2). The choice of placing
the BPR is due to precipitation of solid material right after the HCl addition that is fully
dissolved throughout the acetic acid coil. The HCl precipitation was done by collection of the
two streams in a flask. A number of different pumps were used, all of them being positive
displacement pumps for dosing purposes. Knauer Azura P 2.1S HPLC pumps with 10 mL
stainless steel pump heads (P1 and P2) were used for the 10,10ꢀDMA (1) and DMPCꢀMgCl (2);
a Syrris Asia pump (dual pump) equipped with 0.5 and 1.0 mL glass syringes was used for both
hydrochloric acid (P3) and acetic acid (P4). A MerckꢀHitachi HPLC pump with a 10 mL
stainless steel pumphead was used for the aqueous ammonia (P5) and Ismatec Reglo RH00
piston pumps were used for the decanter outlet (P6) and the 2 M HCl in Et2O (P7). The two
Knauer pumps were specially ordered with PTFE gasket intended for Grignard reagents and THF
solvent. The remaining pumps were chosen based on availability in the laboratory. The flow rate
was determined in accordance with the maximum capacity of each pump and the limitation was
the pump used for the acetic acid.
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Figure 4: Flow sheet of the flow reactor setup for the redesign of the Melitracen HCl synthesis.
Pump (P), Coil (C), Tꢀmixer (T), Infrared Inꢀline flow cell (IR), Back pressure regulator (BPR).
Results and Discussion
Stepwise Verification of Flow Reactor Parts
A stepwise implementation and verification of each step was done to minimize the risk of
operational problems, while operating the entire setup as illustrated in Figure 4. The major risks
were considered to be clogging issues and separation performance.
The Grignard addition of DMPCꢀMgCl 2 to 10,10ꢀDMA 1 was the first part to be verified and
an equivalence of 1.1 DMPCꢀMgCl 2 was used to ensure full conversion of 10,10ꢀDMA 1. Only
a few minutes of residence time were needed for the reaction to achieve full conversion of the
10,10ꢀDMA 1. The reaction was easily followed visually, as the magnesium alkoxide 3 becomes
dark red/orange. The product stream was collected in a flask, where it turned to a more orangeꢀ
like appearance over time.
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Implementation of the HCl stream for hydrolysis and dehydration caused boiling of the THF
solvent, but full conversion was achieved within minutes. Implementing the acetic acid stream
resulted in some alteration of the setup to account for the boiling of the THF, as full conversion
was not achieved. A back pressure regulator (BPR) of 100 psi was added to prevent the boiling
of the THF (65 °C at STP). The BPR provided a stable flow that ensured a steady residence time
in the HCl coil (C2), resulting in the desired full conversion of the magnesium alkoxide 3 to the
dehydrated product 5. Adding the aqueous ammonia stream to the setup caused precipitation of
ammonium chloride salt. The precipitate was easily dissolved by addition of water. Due to lack
of pumps, it was decided to dilute the acetic acid to 40% from the original 80% and to double the
flow rate. From a production perspective, an additional pump with water would be better suited
as 80% acetic acid is the standard concentration in production. Acetic acid serves to assure that
the magnesium salt complex remains soluble after pH adjustment to basic conditions. The BPR
was originally implemented right after the HCl coil, but the white solid precipitate later caused
clogging of the BPR, so it was moved to be after the acetic acid stream where a full liquid
homogeneous phase was present. The choice of not moving it to be after the aqueous ammonia
coil was due to a small risk of having precipitation upon the addition thereof, as this was
observed in a previous run. At the end of the acetic acid addition during all adjustments, a full
oneꢀphase homogeneous stream was constantly present and it was considered more stable to add
the BPR at this point in case of any fluctuation.
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Having the entire setup running, the decanter was tested for the setup. A previous flow setup
had proved the decanter’s capability for separating organic and aqueous phases from each other,
so that a single experiment was enough to demonstrate the decanter for this separation. The last
stream to be implemented was the 2 M HCl (Et2O) stream for crystallization. At first, mixing of
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the two streams was attempted in a Tꢀmixer (2.5 mm ID), but the low pressure pumps used
(Ismatec pumps) could not deliver a high enough pressure to avoid clogging. The clogging was
caused by evaporation of the solvents due to the low boiling points of both THF and Et2O and
the crystallization of Melitracen HCl (6) happening in the Tꢀmixer. As an alternative, the two
streams (P6 and P7) were pumped individually into the collecting bottle. No optimization was
done to control the crystallization, as this was not the scope of the project, and for a fullꢀscale
setup HCl gas would be a preferred choice. Figure 5 shows the fractions collected from the setup.
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Figure 5: The collected fractions of product streams from the setup during continuous operation.
To the left is the aqueous waste from the decanter, at the center is the organic phase containing
dehydrated product 5 and to the right is the crystalline Melitracen HCl 6 API and the mother
liquid.
Operation of Full Flow Setup
The final flow setup, as illustrated in Figure 4, was operated for 300 minutes under steady state
conditions. The experiment was terminated at the point of complete utilization of the 2 M HCl
(Et2O). For the first 30 minutes the setup was not in steady state due to a tube burst and fittings
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around the IR flow cell, but a steady state was achieved shortly after replacement of the broken
fittings. The tube burst was a result of a clog formed from Grignard reagent reacting with
residual water in the IR flow cell from previous cleaning. The flow rate of the system is given in
Table 2 and Table 3 provides the residence times in the important parts of the reactor.
Table 2: The reactor configurations and residence times, along with important observations, for
the Melitracen HCl 6 synthesis as operated with the flow setup (Figure 4).
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Reactor part
Coil 1
Flow Rate
(mL/min)
4.5
Reactor
Volume (mL)
4.95
Residence
Time (s)
66
Observation
Deep red color from reaction.
Temperature higher than ambient,
lower than the boiling point of THF.
Temperature is above the boiling
point of THF, 100 psi suppress
boiling.
Coil 2
5.5
1.98
21.6
Stream becomes transparent with a
white solid that disappears into an
oneꢀphase system.
pH < 2
Coil 3
Coil 4
8.0
9.9
0.99
1.98
100
7.4
6.0
Oneꢀphase system
pH < 2
Twoꢀphase system
pH > 10
Decanter
(Org/Aq)
9.9 (4.5/5.4)
606.1
Twoꢀphase system
pH > 10
Table 3: The flow rates and concentrations of the different reactants used in the flow setup.
Reactants
10,10ꢀDMA 1
DMPCꢀMgCl 2
HCl (aq)
Flow rate (mL/min)
Concentration (M)
1.8
Equivalence to 10,10ꢀDMA 1
2.0
2.5
1.0
1.5
1.05
3.33
4.86
7.07
1.0
12 (37%)
7 (40%)
AcOH (aq)
NH3 (aq)
2.50
1.9
13.4 (25%)
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HCl (Et2O)
2.25
2
1.25
5
6
7
8
9
An IR flow cell was placed after coil 1 and was used to follow and ensure that full conversion
of 10,10ꢀDMA 1 was achieved. Figure 6 shows the carbonyl peak of the 10,10ꢀDMA 1 as it
progressed throughout the experiment. The trend line absorbance intensity of the peak is based
on area to zero baseline for the IR region of 1610ꢀ1580 cmꢀ1 and is given in arbitrary units. The
offꢀline HPLC data in Table 4 confirms full conversion of 10,10ꢀDMA 1. The replacement of the
tubing caused an exposure of the magnesium alkoxide 3 to the surrounding atmosphere (i.e.
moisture in the air), resulting in the deposit of magnesium salts on the IR diamond window.
Despite an attempt to clean the window, some deposit was still present, causing the small offset
from the zero baseline, which explains why zero is not achieved.
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10,10-DMA
Carbonyl Peak
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HCl (aq) Pump
stopped briefly
Out of HCl 2M
in Et2O
Stable Flow
Sample
No. 1
Sample
No. 2
Sample
No. 3
Sample
No. 4
Sample Sample SampleSample
No. 5 No. 6
No. 7 No. 8
0
0
0
50
100
150
200
250
300
350
Time (min)
Figure 6: The IR data on the flow setup run, following the peak of the carbonyl functional group
of 10,10ꢀDMA (1) and the reference samples for offꢀline HPLC analysis given in Table 4. Steady
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state conditions were achieved after 30 minutes; the initial 30 minutes of unstable flow were
related to bursting and replacing of tubing and fittings.
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A portion of the Melitracen HCl (6) was collected by filtration in a Büchner funnel, washed
with THF and dried in a vacuum oven at 50 °C for 24 hours. The product was subjected to
complete release analysis for the API and all product attributes were found to be within
specification. A total of 300 g of dry Melitracen HCl (6) was isolated from the flow setup,
requiring a consumption of approximately 240 g 10,10ꢀDMA (1) starting material.
Table 4: The HPLC samples, where samples were collected from the aqueous waste stream of
the decanter, the crystallized Melitracen HCl (6) and the mother liquid, and a few from the
organic phase of the decanter.
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Sample
No.
Compound
Crystallized
Product
(Area%)
100
nd
Mother
Liquid
(Area%)
97.65
nd
Decanter
Aqueous
(Area%)
62.0
38.0
nd
Decanter
Organic
(Area%)
No sample
1
2
3
4
5
Melitracen (5 or 6)
Alcohol (4)
10,10ꢀDMA (1)
Other Impurities
Melitracen (5 or 6)
Alcohol (4)
10,10ꢀDMA (1)
Other Impurities
Melitracen (5 or 6)
Alcohol (4)
10,10ꢀDMA (1)
Other Impurities
Melitracen (5 or 6)
Alcohol (4)
nd
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nd
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nd
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nd
2.0
37.8
62.1
nd
No sample
No sample
No sample
No sample
nd
0.2
nd
100
nd
nd
96.3
nd
3.5
20.5
79.5
nd
nd
0.2
nd
100
nd
nd
99.0
nd
0.8
nd
100
nd
10,10ꢀDMA (1)
Other Impurities
Melitracen (5 or 6)
Alcohol (4)
nd
0.2
nd
99.9
0.1
99.1
nd
nd
100
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10,10ꢀDMA (1)
Other Impurities
Melitracen (5 or 6)
Alcohol (4)
10,10ꢀDMA (1)
Other Impurities
Melitracen (5 or 6)
Alcohol (4)
10,10ꢀDMA (1)
Other Impurities
Melitracen (5 or 6)
Alcohol (4)
10,10ꢀDMA (1)
Other Impurities
nd
nd
0.7
0.2
99.3
nd
0.5
0.2
39.8
60.2
nd
nd
nd
6
7
8
100
nd
nd
nd
100
nd
100
nd
nd
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nd
nd
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100
nd
nd
39.3
60.7
nd
99.8
0.2
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nd
nd
nd
100
nd
nd
56.4
43.6
nd
26.2
73.8
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100
nd
nd
nd
nd
nd
nd
Conclusions
A full redesign of a current batch synthesis to a full flow setup has been possible, from the
starting material to the final salt crystallization of the active pharmaceutical ingredient,
Melitracen HCl. The flow process was significantly simplified compared to the batch process,
with removal of a phase separation and usage of tetrahydrofuran (THF) only as a solvent
compared to the previous tolueneꢀTHF solvent mixture. All synthetic steps were carried out at
ambient temperature, whereas routine batch production requires active heating (up to 50°C) and
cooling in several steps. The crystallization of the Melitracen HCl was proven possible in THF
with 2 M HCl in diethyl ether (Et2O) and eliminated a solvent swap to ethanol. The
crystallization was not optimized and would most likely be done with HCl gas, with an expected
additional gain in yield from the lower volume of solvent. The isolated yield in the given study
was approximately 85%. The phase separation achieved with the decanter was higher than 99%
product in the organic phase, with a HPLC purity of greater than 99%. The isolated Melitracen
HCl was analyzed in accordance with the inꢀhouse release methods required for current batch
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production and all measurements were in accordance with requirements. A production of 60 g/h
of isolated Melitracen HCl can be achieved with the flow setup. Furthermore, the setup
demonstrated great robustness towards fluctuations in reactant streams. The oneꢀstep hydrolysis
and dehydration could potentially be applicable for other Grignard additions, as could the
subsequent decanter phase separation.
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Corresponding Author
*Telephone: +45 45 25 28 27. Fax: +45 45 88 22 58. Eꢀmail: sk@kt.dtu.dk
Acknowledgement
The authors gratefully thank H. Lundbeck A/S for financial contribution throughout the case
study of transforming the routine batch process to a flow method.
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