Broad spectrum chemistry as practised by Novartis process research

Article abstract of DOI:10.2533/000942904777677533

Three actual examples from the current product palette within Novartis Process Research will demonstrate the some of the variety and challenges encountered in modern chemical development.

Full text of DOI:10.2533/000942904777677533

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CHIMIA 2004, 58, No. 9
Chimia 58 (2004) 640–648
© Schweizerische Chemische Gesellschaft
ISSN 0009–4293
Broad Spectrum Chemistry as Practised
by Novartis Process Research
Stuart J. Mickel*, Reto Fischer, and Wolfgang Marterer
Abstract: Three actual examples from the current product palette within Novartis Process Research will demon-
strate the some of the variety and challenges encountered in modern chemical development.
Keywords: Aldol · Dakin-West · Dimroth · Discodermolide · Nitration
1. Introduction
how mechanistic considerations can be of
The synthesis from research (Scheme 1)
immense value in attaining a safe repro- was relatively straightforward, however, for
Modern chemical development faces a ducible scalable process.
formidable challenge in converting the
the following main reasons, we elaborated
an improved, alternative synthesis for
scale-up in the pilot plant and towards fu-
ture production:
wonderful set of reactions and reagents
which are published in the chemical litera- 2. CGP59326 New Process
ture every day, into workable reliable
1) The use of a benzyl protecting group for
the pyrrole amine functionality was
mandatory for the outlined synthetic
strategy, however, deprotection turned
out to be technically unfavourable be-
cause it required a large excess of alu-
minium trichloride which subsequently
had to be quenched and disposed of.
2) The classical, three-component pyrrole-
forming condensation reaction was low-
yielding.
processes. Normally this ‘state of the art’
Pyrrolo[2,3-d]pyrimidine-derivative 1
chemistry is described to function, usually (Fig.1) was manufactured in 100 kg scale
on a very small scale, but its conversion to for clinical investigation as an exploratory
a scaleable reproducible process provides anti-tumour agent [1].
the development chemist with a set of se-
vere problems. The variety of structures
that can be encountered by the development
chemist is vast and ranges from antibiotics
to tertasaccharides. The array of issues with
which a development chemist is confronted
is equally as large, from environmen-
3) The pyrimidine cyclisation step in boil-
ing formic acid raised safety concerns
and resulted in dark coloration of the
product which made cumbersome pu-
rification procedures necessary.
tal/health and safety concerns to polymor-
phism and the properties of solids. In this
article we would like to highlight some of
these challenges by referring to a selection
of three recent projects from our depart-
4) The hydroxy- as well as the chloropy-
rimidine intermediates had extremely
poor solubility which resulted in dilute
ment. These will demonstrate how some of
the issues encountered in the daily business
Fig. 1.
of chemical development may be solved.
In the first example a short overview of
the development history of a relatively sim-
ple compound will show how the elabora-
tion of alternative synthesis concepts – even
in the field of well-known heterocycles –
can indeed lead to economically as well
as ecologically superior manufacturing
processes. It also demonstrates the value of
re-examining ‘old’ reactions and shows
*Correspondence: Dr. S.J. Mickel
Chemical and Analytical Development
Novartis Pharma AG
CH–4002 Basel
Tel.: + 41 61 696 29 52
Fax: + 41 61 696 29 57
E-Mail: stuart_john.mickel@pharma.novartis.com
Scheme 1.

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CHIMIA 2004, 58, No. 9
to form the acylamino ketone (Scheme 3) literature. The results were convincing: 1
reactions and a large excess of phos-
phorus oxychloride being used for the
chlorination step.
[6].
equiv. of acetic acid made it possible to run
After some of our own investigations the reaction in an addition-controlled mode
confirmed the mechanism outlined above, with carbon dioxide evolution being directly
we concluded that the following kinetic in- linked to alanine addition. As an extra bene-
terpretation would at least partly explain the fit, acetic anhydride and pyridine excess
peculiarities of the Dakin-West reaction: as could now be significantly reduced.
2.1. Development Synthesis
Strategy
For the synthesis of 1, we concluded
that 2-amino-3-cyano-4,5-dimethylpyrrole
(2) (Fig. 2) was the intermediate of choice.
Its simple synthesis from 3-amino-2-bu-
tanone and malonodinitrile was already de-
scribed more than 40 years ago [2] and it is
sufficiently stable towards air oxidation to
allow normal handling in a production fa-
cility.
we see in Scheme 3, the ring-opening hy-
In a second step, the reaction was suc-
drolysis of acylated azlactone formally re- cessfully adapted to the modified Dakin-
quires 1 equiv. of water. Since there are cer- West procedure with triethylamine/DMAP,
tainly not sufficient quantities of water in a introduced by Steglich and Höfle in 1969
boiling reaction mixture of excess anhy- [7] which requires much smaller amounts
dride and pyridine, this ‘water-equivalent’ of anhydride and base and is therefore eco-
has to come from the formation of acetic nomically more advantageous. Eventually,
anhydride from acetic acid. Acetic acid it- over 0.5 kmol alanine were successfully
self is formed in the first two steps of the re- converted to acetylaminobutanone 3 in a
action sequence, namely N-acylation and 400 l reactor in over 90% yield with carbon
azlactone condensation. Therefore its ini- dioxide evolution (~ 11’000 l!) being in a
tial concentration in the reaction mixture is virtually linear relation to alanine addition.
very low and hence azlactone hydrolysis is The crude product solution was concentrat-
very slow. Once the mixture is heated and ed by evaporation of acetic acid, acetic an-
N-acylation of alanine starts to increase the hydride, and triethylamine. This concen-
acetic acid concentration increases rapidly trate was diluted with water and malono-
and therefore azlactone hydrolysis is accel- dinitrile and the resulting solution added to
erated. The following decarboxylation is 30% sodium hydroxide whereby pyrrole 2
virtually spontaneous. This results in the re- was formed and precipitated in an extreme-
action having a typical, self-accelerating ki- ly fast, exothermic but fully addition-con-
netic, which is exactly what you do not trolled reaction [8]. Crystalline pyrrole 2
want to have in a pilot or production plant, was directly isolated by centrifugation,
particularly not if equivalent amounts of washing with water and drying and did not
From this pyrrole we intended to modi-
fy the pyrimidine ring formation in such a
way that no protection was necessary and
the need for formic acid was eliminated.
Fig. 2.
gas are formed during a reaction.
require further purification [9]. Neither dis-
To test this hypothesis, we performed ex- tillate nor mother liquor required any spe-
periments where we added various amounts cial treatment. This procedure for the syn-
of acetic acid to the initial mixture of acetic thesis of pyrrole 2 (Scheme 2) is very effi-
anhydride and pyridine – an idea which sur- cient, high-yielding (83–85% over 2 steps
prisingly has never been investigated in the calculated from alanine) and requires only
two standard reactors.
2.2. Pyrrole Synthesis
α-Acylamino ketone 3 [3] is not com-
mercially available but easily accessible
from alanine and acetic anhydride, a reac-
tion that was initially described by Dakin
and West in 1928 [4] and therefore is known
as the Dakin-West reaction. Since
(racemic) alanine is very cheap, this
seemed to be an attractive approach to the
synthesis of pyrrole 2 (Scheme 2).
However, there is one major drawback
to the Dakin-West reaction regarding its
scale-up to plant scale: it is accompanied by
an uncontrolled formation of carbon diox-
ide, which is absolutely prohibitive on tech-
nical scale. Our initial attempts to control
formation of carbon dioxide by variation of
reaction parameters all failed and addition-
ally never produced yields which were at
least comparable to the standard protocol.
So we decided to examine the reaction
mechanism in more detail.
Scheme 2. Pyrrole synthesis
Even though the Dakin-West reaction
can hardly be considered well-known,
there is quite a lot of published work in-
cluding some very detailed mechanistic
investigations particularly by Steglich [5].
It is generally accepted that the mecha-
nism involves dehydrative formation of an
azlactone (oxazolinone) which is then C-
acylated (in equilibrium with O-acyla-
tion), and then undergoes ring-opening
hydrolysis followed by decarboxylation
Scheme 3. Published mechanism of the Dakin-West reaction

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2.3. Pyrimidine Ring Synthesis
and upon isolation identified as amidine 4c able for production in standard equipment
In 1964, Taylor and Hendess reported a which now seemed to be the reactive of a multi-purpose plant [16]. In addition –
procedure to convert an unprotected amino- species towards the formation of the pyrim- to the best of our knowledge – this is the
cyano-pyrrole into an aminopyrrolopyrimi- idine ring [12]. This optimised and simpli- first application of a Dakin-West reaction
dine derivative with trimethyl orthoformate fied process was run in the pilot plant on on a technical scale.
and ammonia [10]; however the very scarce 0.45 kmol scale. Chloroaniline and triethyl
use of this method in the newer literature orthoformate were dissolved in ethanol and
seemed to indicate a somewhat limited the pH of the solution was adjusted to 5.5 3. Discodermolide
scope. We reasoned that in principle, it by addition of acetic acid. Pyrrole 3 was
should be possible to apply this type of then added over a few hours at 45–50 °C;
The second example demonstrates the
pyrimidine ring formation to pyrrole 3 un- after cooling, precipitated pyrrolopyrimi- power of modern organic chemistry and al-
der carefully optimised conditions which dine 5 was centrifuged off, washed and so highlights some of its limitations. We
avoid side reactions at the pyrrole ring ni- dried. The yield in the pilot plant was over were asked to prepare a significant amount
trogen. To explore this, we initially pre- 80% (based on pyrrole 3).
of a rare natural product, (+)-discoder-
pared iminoester 4a (Fig. 3) from pyrrole 3
Chlorophenyl-pyrrolopyrimidine 5 now molide 6 (Fig. 4).
and triethyl orthoformate.
only needed to be converted to its isomer 1.
The crude iminoester was then treated This isomerisation is referred to as the Dim-
with 3-chloroaniline. This sequence under roth rearrangement [13]. For pyrrolopyrim-
various conditions at best produced moder- idines, it is very rarely reported in the liter-
ate yields of 3-chlorophenyl-pyrrolopyrim- ature [14], with only a few more examples
idine 5 (Scheme 4) in rather unsatisfying for other pyrimidine derivatives [15]. Lab
quality. Therefore, the reaction sequence trials led to the conclusion that in this par-
was changed: iminoester 4b was formed ticular case, no catalyst was required and
from 3-chloroaniline and triethyl orthofor- reaction temperature was the most impor-
mate under acid catalysis [11] and isolated tant parameter. A mixture of ethylene gly-
as a crude oil. Pyrrole 3 was then treated col, ethanol, and water eventually turned
with iminoester 4b. This procedure turned out to be optimal; clean isomerisation could
out to be superior particularly after optimi- be achieved in over 90% yield by simply re-
Fig. 4. (+)-Discodermolide ((+)-6)
sation of solvent, acid catalyst and pH.
fluxing for a few hours. Upon cooling, the
This compound was first isolated in
We concluded that the mechanism of product precipitates and can once again be 1990 from a rare deep sea sponge (Disco-
this pyrimidine ring formation involves a isolated as a white solid by filtration, wash- dermia dissoluta) by workers at the Harbor
series of orthoester-iminoester-amidine ing and drying. This procedure was suc- Branch Oceanographic Institute in Florida
equilibria. Hence, it should even be possi- cessfully run in the pilot plant in 0.3 kmol [17]. It is a microtubule stabilizing agent and
ble to run the reaction under kinetic control scale (Scheme 4).
has demonstrated efficacy in human tumour
The drug substance free base was growth inhibition in hollow fibre and
without preformation of any iminoester in-
termediate. In agreement with our expecta- brought in its mesylate salt form by crys- xenograft mouse models [18]. The com-
tions, we found, that under carefully opti- tallisation from ethanol/water in the pres- pound is produced by the sponge in very
mised conditions, the three-component re- ence of methylsulfonic acid and final re- small quantities around 2 mg/kg per dry
action of pyrrole 3, triethyl orthoformate, crystallisation from acetone/water, yielding weight of sponge: therefore the only reason-
and chloroaniline proceeded relatively a white powder with high purity (HPLC as- able way to procure quantities of this com-
slowly but was surprisingly clean. This for- say >99%) which met all internal specifica- pound for clinical evaluation is total synthe-
mation of pyrrolopyrimidine 5 turned out to tions and was subsequently released for use sis.
be distinct from the initial procedure be- in humans.
cause only trace amounts of iminoester 4b
In summary, a very efficient, cost effec- 3.1. Problem Analysis
Structurally, discodermolide (6) con-
stead, a new, major intermediate was found facturing of 1 was developed, which is suit- sists of a linear polypropionate chain con-
were detected in the reaction mixture. In- tive and ecological process for the manu-
Fig. 3.
Scheme 4. Final pilot plant route

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taining thirteen stereocentres, six of which
are hydroxyl-bearing, with one of these es-
terified as a γ-lactone (C(5)) with another as
a carbamate (C(19)). It also features seven
methyl-bearing stereocentres and three (Z)-
configured alkenes, one of these being part
of the terminal diene unit another being a
cis trisubstituted system at C(13)–C(14)
which offers a synthetic challenge in con-
trolling the stereochemistry. Also present in
the structure is a common stereo triad
(methyl, hydroxyl, and methyl) that is re-
peated three times.
The synthesis of this compound posed a
real challenge for chemical development.
Alone the number of steps required (36), to-
gether with the number of chromatographic
purifications (around 17) appeared to make the
project prohibitive. However, in view of the
projected dose we decided to go ahead with
the synthesis of around 60 g target quantity.
We scanned the available literature and
at that time discovered around five total
syntheses described [19] together with a
number of publications describing frag-
ment synthesis [20]. A useful review of the
available synthetic approaches has recently
been published [21]. A working group was
established to evaluate the chemistry de-
scribed in these published approaches. We
analysed them with respect to a number of
criteria, e.g. problematic reagents, changes
in oxidation state, number of chromatogra-
phy passes and so on. Many of the reactions
Scheme 5: Abbreviated synthetic scheme for (+)-discodermolide with numbering scheme
described were deemed to be not practica-
ble on any sort of significant scale. For ex-
ample, Smith et al. reported [19e] a high-
pressure reaction for the synthesis of an ad-
vanced intermediate phosphonium salt (12
Kbar), investigations on this crucial step
have recently been published [22]. This was
not an option for us. In some of the other
routes we came across non-stereoselective
reactions, low molecular weight acetylenes
(thermal stability problems), lots of chro-
matography, and no (or very few) crys-
talline intermediates. One synthetic chal-
lenge was certainly the formation of the
C(13)–C(14) trisubstituted cis double bond.
Numerous ingenious ways have been de-
vised to construct this structural feature.
For example Paterson et al. employed a
selenium Claisen rearrangement [19h],
Arefolov and Panek [20b] utilised some
acetylenes combined with attractive zirco-
nium chemistry to set up this structural fea-
ture. Unfortunately these two attractive
routes were not an option for us on the large
scale. The crystallisation of discodermolide
was also not defined by any of the authors.
This is a very important point for the devel-
opment chemist, as it must be ensured that
the correct crystal modification is formed.
We finally settled on a combination ap-
proach of the synthesis of Prof. Smith for
the first part of the route merging with that
of Prof. Paterson for the latter part of the
large-scale synthesis [23]. An abbreviated 3.2. Some Problem Steps
synthetic Scheme is shown in Scheme 5.
Some of the ‘named bond forming reac-
Starting from the readily available ester tions’ used in the synthesis are shown in
7 a common intermediate, amide 8, was Fig. 5.
prepared in six steps. This compound con-
In this entire synthesis of some 36 steps
tains the repeating stereo triad present in 6. there are many ‘problem steps’ which can
Thus, suitable manipulation leads to the be identified. Three of these will be briefly
three advanced intermediates 9, 10, and 11. discussed in the following section.
After Suzuki coupling of 9 and 10 to pro-
duce fragment 12 further elaboration into 3.2.1. Cis Vinyl Iodide
the Paterson synthesis eventually produces
As indicated above the introduction of
the advanced aldehyde 13, which is then the C(13)–C(14) cis substituted double bond
coupled in a final aldol reaction with ketone unit is especially challenging. We chose to
11. Three final steps then deliver the final employ the Zhao olefination [24] procedure,
product 6 [23].
as described by Smith et al. [19e] and Mar-
Fig. 5: Reactions em-
ployed in the synthesis
of (+)-6

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shall and co-workers [19g], depicted in
Scheme 6 to prepare the cis vinyl iodide pre-
cursor for this structural unit.
This reaction is fraught with problems,
all the parameters one can imagine, e.g.
time, temperature concentration, order of
addition, work-up, chromatography, and so
on, are critical in this process. We obtained
the desired cis-vinyl iodide 9 in 31% yield
after chromatography purification on silica
gel. Only small amounts of the undesired
trans isomer were detected (cis/trans 15:1),
this can be easily removed at the next step.
We did not observe any des-iodo olefin
(compound A, Scheme 6) suggesting that
the iodination of the phosphonium salt via
ylide iodination had been completed before
it was added to aldehyde 14.
This olefination step was one of the
most difficult reactions for scale-up. We
consistently obtained 25–31% yield on the
maximum scale of 2.5 kg of aldehyde 14.
Scheme 6. Route to cis vinyl iodide
Complicated work-up procedures and in-
stability of 9 contributed to the low yield.
Elemental iodine has been utilised for the
conversion of ethyltriphenylphosphonium
iodide into the iodo ylide. We found that N-
iodosuccinimide can be used to replace io-
dine without detriment. While this makes
the reaction easier to handle, it did not con-
tribute to an increase in yield. Initially, we
observed the formation of the methyl ke-
tone B [24] during the work-up. This by-
product can be avoided by using non-aque-
ous work-up.
Smith and coworkers [25] reported that
the reaction of the iodo ylide with 14 af-
forded epoxide C in addition to the desired
9 in a 1:1 ratio.Alternative approaches were
investigated to minimize this major by-
product, however, they were unsuccessful.
For example employing a method described
by Shenand Gao [26] where the initially
formed betaine intermediate was deproto-
nated with a second equiv. of base and then
iodinated, produced des-iodo olefin A. Uti-
lizing Hanessian’s phosphonates [27] in
this process also resulted in only des-iodo
olefin A.
Scheme 7. Paterson aldol reaction
3.2.2. Paterson Aldol
in low yield or not at all. The reagent 6) A solvent change is necessary before
quality is not definable.
beginning the oxidative work-up.
This is a mis-matched aldol reaction
where the stereochemical bias of the reac-
tion is overturned by the chiral nature of the
reagent (Scheme 7) [19h][28].
2) The presence of traces of moisture 7) Aqueous quench and evaporation of
causes isomerisation of cis enal nearly
quantitatively to the trans enal, which
then takes part in the aldol reaction
producing aldol 17.
the reaction mixture (before oxidative
work-up) leads to significant decom-
position of the product and its epimer.
8) Oxidative work-up leads to significant
decomposition of the product and its
epimer.
This turned out to be a very capricious
reaction and achieving reproducibility was
(and still is) a tremendous challenge. After
extensive small-scale experimentation sev-
eral factors were determined to be respon-
sible for this lack of reproducibility:
1) Reagent quality: DIP-Cl is a low
melting, extremely air and moisture
sensitive unstable compound. At tem-
peratures above 0 °C it eliminates one
molecule of pinene. Depending on the
reagent quality the aldol either worked
3) The enolate formation is complicated
by an internal (Claisen) cyclisation re-
ducing its availability for aldol reaction. 9) The product is not very stable to chro-
4) Large excesses of enolate (6.6 equiv.,
based on aldehyde 13) are required to
push the reaction to completion, com-
plicating work-up and purification.
matography on normal-phase silica-
gel but stable to reverse-phase condi-
tions.
10) The product is not crystalline.
With all these problems how was a re-
5) The ratio of epimers, 3.5–4.0:1, is best
obtained using diethyl ether as a solvent. producible process obtained?

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A (+)-DIP-Cl supplier was found who
produced the compound as a 70% solution
in hexanes. This solution is, according to
the manufacturer, indefinitely stabile, even
at room temperature. Utilising the reagent
in this form immediately solved the repro-
ducibility problems. The reaction went to
completion (complete consumption of alde-
hyde 13) with little to no isomerisation to
the trans enal being observed! However, on
scale-up (100 mg to 50 g of 13) the lab yield
of 45% of 16 was not achieved, 20% being
obtained.
We examined the fate of 16 throughout
each stage of the work-up and discovered
that it was apparently not stable. The reason
for this instability is not clear but may be
related to the large excesses of reagents
Scheme 8. Final steps of the synthesis of (+)-6
which are required to drive the reaction to
completion.
The solution was to eliminate the work-
up steps entirely and directly chromato- ter 85:15 at pH 4 the lactone was the only sequent reduction of the nitro group to an
graph the reaction mixture without work- product isolated as sandy crystals in 95% amine. It also shows an important aspect of
up! This provided a 60% yield of the de- yield. The polymorphic form (mono-hy- process research, the avoidance of toxic
sired epimer. Thus 700 g reaction mixture, drate) that was obtained by the above recrys- intermediates.
containing around 12% of the desired prod- tallisation method was highly reproducible.
uct, was diluted with 368 kg of
MeCN/TBME/H2O 85:15:10 and applied the cleavage process [30] (Fig. 6), they are [31] may be seen as an example of how the
The recent multi 100 kg preparation of
Several side products are formed during the CNS-active substance AAG561 (20)
to
a 120×30 cm column containing easily separated by chromatography. Treat- drawbacks of an early synthesis route, bur-
20 kg RP-18 reverse-phase silica-gel. ment of (+)-6 itself with acid also produces dened with mutagenic intermediates and
The column was eluted with 1060 kg the same set of compounds. Their forma- purification problems, may bring ‘well-
MeCN/TBME/H2O
85:15:10
then tion demonstrates the propensity of (+)-6 to known’ heterocyclic chemistry into the fo-
MeCN/TBME 1:1 collecting 20 kg frac- cyclise via participation of the C(13)–C(14) cus of interest of process development. A
tions. The product fractions were combined double bond.
new shortened synthesis route was success-
and partially evaporated and the residue ex-
That over 60 g of (+)-6 could be pre- fully implemented for AAG561 at an al-
tracted with ethyl acetate and re-evaporated pared by this route is a tribute to the power ready advanced development stage, which
to give 150 g of pure aldol product 16. of modern chemistry and its proponents. simplified the preparation considerably by
These conditions remove the ‘reactive com- The entire process took some 20 months to replacing the benzthiadiazole 21 as the cru-
ponents’ which presumably initiate the de- complete, an average of one step per fort- cial intermediate with the quinoxaline 22
composition. Isolated 16 was found to be a night. Surprisingly, most of the steps were (Scheme 9).
stable compound.
transferred to larger scale without any great
The established five-step procedure
problems. We identified around seven prob- for 21, employing 2-nitro-6-methylaniline
lematic steps, of which three occur early in (23) as the starting material, was based on
3.2.3. Final Step
The final step in the sequence leading to the route. The end game is far from ideal, S-protection of the phenylendiamine
(+)-6 is shown in Scheme 8.
after such a synthetic sequence the final few motif for further Cl/N-functionalisation.
This desilylation reaction of 18 (ob- steps leading to the final drug substance However, this involved several mutagenic
tained by Evans-Saksena reduction [29] of need to be kept ‘simple’. The arduous chro- reagents and intermediates that dictated
16 with tetramethylammonium triacetoxy- matography of the aldol coupling product is extra purification operations for the
borohydride) is very complex. The first, clearly not practical to move into produc- process intermediates and a properly con-
rapid reaction is cyclisation to 19 followed tion, fortunately, the predicted low dosage trolled working environment in the pilot
by slow cleavage of the various silyl levels should keep the yearly manufactur- plant. Additionally for the last steps to-
groups. All the possible combinations of ing requirements to a minimum.
wards the active substance 20 the benz-
bis-silyl intermediates can be observed in
One major problem associated with a thiadiazole had to be deprotected by re-
the LC of this reaction. The slowest silyl synthesis of this length is the proper labora- duction and capped with glyoxal in two
group to hydrolyse is that at the 3-position. tory examination of the later reactions in a additional steps. The use of the quinoxa-
The reaction is a fine balance between de- sequence. Initially there are no answers to line 22, as a synthon with the full final
sired and undesired processes (side product these supply problems; one just has to run functionalisation pattern, circumvented
formation) and must be closely monitored. the small-scale reaction and hope that on all of the inherent problems of the benz-
Chromatography on reverse-phase sili- transfer to larger scale the reaction proceeds thiadiazole route(s).
ca-gel with an acetonitrile/water mixture as expected.
delivered (+)-6 in 70% yield. The compound
The straightforward five-step procedure
towards the new key intermediate 22 is out-
lined in Scheme 10 [32].
thus isolated was shown by HPLC to be a
mixture of lactone and the corresponding hy- 4. AAG561, New Process
droxy acid (92:8). This equilibrium was re-
A priori, the crucial reaction was ex-
pected to be the nitration of 26 to 27 since
adjusted completely to the lactone side by
The third and final example of process the literature precedence with nitration of
lowering the pH with hydrochloric acid. research and development deals with new electron-deficient quinoxalines, or 6-halo-
Thus on crystallization from acetonitrile/wa- aspects of nitration chemistry and the sub- quinoxalines, was quite discouraging [32].

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With some delight we found that the 8-
methylgroup in 26 (or other 8-
methylquinoxalines) sufficiently activated
the homocyclic ring for a selective and effi-
cient C(5)-nitration in mixed acid at 45 °C.
The nitration product 27 could be isolated
in high yield and quality by direct crystal-
lization. In the absence of the activating 8-
methyl group unspecific side reactions
dominated. The side-products (<10%) in
the nitration mixture of 26, resulting from
oxidative dehalogenation at C(6) 28 or
chlorination at C(7) 29, inferred the pres-
ence of nitrylchloride which in turn led to
extensive technical measures in order to
scrub this volatile and environmentally
problematic compound from the process
exhaust. Interestingly, the nitration of 26 in
an ionic liquid with nitric acid at 80 °C
takes a completely different turn and leads
in a rather sluggish reaction via mononitra-
tion at C(7) 30 to a C(5),C(7)-dinitrated
product 31, that is not detectable in the
mixed acid nitration of 26 [33].
The manufacture of the quinoxaline 27
was scaled up at the site of an external con-
tractor, according to the new nitration route.
For the reduction step 27 to 22, as an al-
ternative to our hydrogenation protocol
(Raney nickel in ethanol, Scheme 9), a high-
yielding Bechamp reduction procedure was
used for the scale up which unexpectedly led
to 2–3% of the rearranged regioisomer 32
(Scheme 11), presumably due to the extend-
ed contact time of the batch with the iron (II)
salts formed in the reaction. The regioisomer
could not be removed in the work-up, or by
an additional recrystallisation, or in the fol-
lowing chemical transformations to the drug
substance 20. Finally, an elegant rework pro-
cedure was found, which exploited the dif-
ferent solubility of the weak bases 22 and 32
in equilibrium with their soluble hydrochlo-
ride salts in water/ethanol mixtures, to re-
crystallise the pure 22 with an excellent re-
covery yield [34].
Fig. 6. Side products from the synthesis of (+)-6
In summary, a simple straightforward
process was developed for the key interme-
diate 22 which is characterised by a good
overall yield, a very high purity, readily
crystallising intermediates which also con-
tributed to the significantly reduced materi-
al flow as compared to the old route.
5. Conclusions
Hopefully, with these three examples
we have been able to provide a flavour for
the breadth and depth of the process
chemists’ field of expertise. The area is of
course much more complex and in process
research one must master, or at least be
conversant with a wide range of disci-
plines.
Scheme 9.
Received: June 18, 2004

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