A New Practical Route for the Manufacture of (4aR, 10aR)-9-Methoxy-1- methyl-6-trimethylsilanyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline

Article abstract of DOI:10.1021/op034112x

Different synthetic routes to the enantiomerically pure octahydrobenzo[g]quinoline derivative JNZ092 were evaluated for their suitability to rapidly prepare a first clinical batch on a kilogram scale. On the basis of the experience of previous octahydrobenzo[g]quinoline projects a new linear synthesis of JNZ092 was established and scaled up successfully. The overall yield was increased by a factor 10 and the preparation time shortened significantly as compared to those of the medicinal chemistry route. As the key strategy all atoms of the octahydrobenzo[g]quinoline skeleton were introduced early by the reaction of the 6-lithiated 1,7-dimethoxynaphthalene with ethyl-2-cyano-3-ethoxyacrylate. As a valuable technological refinement the practicability of a chromatographic technique with repetitive feed injection for the problematic separation of the enantiomers was demonstrated.

Full text of DOI:10.1021/op034112x

Organic Process Research & Development 2003, 7, 904−912
A New Practical Route for the Manufacture of
(4aR,10aR)-9-Methoxy-1-methyl-6-trimethylsilanyl-
1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline
Markus Ba¨nziger,*,† Ernst Ku¨sters,† Luigi La Vecchia,‡ Wolfgang Marterer,*,† and J. Nozulak§
NoVartis Pharma AG, Chemical and Analytical DeVelopment, CH-4002 Basel, Switzerland, NoVartis Institutes for
BioMedical Research, Central Technologies-Preparations Laboratories, CH-4002 Basel, Switzerland, and NoVartis
Institutes for BioMedical Research, Neuroscience, CH-4002 Basel, Switzerland
Abstract:
established during the early development phase. With the
focus on the short-term delivery of the drug substance and
an uncompromised process safety, we succeeded in welding
several synthetic concepts used before in related projects,
such as 24 and 35 (Figure 1), into an improved new synthesis
which could satisfy the immediate demands for kg amounts.
Different synthetic routes to the enantiomerically pure octahy-
drobenzo[g]quinoline derivative JNZ092 were evaluated for
their suitability to rapidly prepare a first clinical batch on a
kilogram scale. On the basis of the experience of previous
octahydrobenzo[g]quinoline projects a new linear synthesis of
JNZ092 was established and scaled up successfully. The overall
yield was increased by a factor 10 and the preparation time
shortened significantly as compared to those of the medicinal
chemistry route. As the key strategy all atoms of the octahy-
drobenzo[g]quinoline skeleton were introduced early by the
reaction of the 6-lithiated 1,7-dimethoxynaphthalene with ethyl-
2-cyano-3-ethoxyacrylate. As a valuable technological refine-
ment the practicability of a chromatographic technique with
repetitive feed injection for the problematic separation of the
enantiomers was demonstrated.
Syntheses Evaluation
The medicinal chemistry route for JNZ092 (1),2 compris-
ing 11 chemical steps as outlined in Scheme 1, was deemed
unsuitable for large-scale manufacture because of several
scale-up difficulties encountered already in bench-scale
experiments during the preparation of clinical supplies for
2, which shared the same intermediate 8 with JNZ092.
Starting from 1,7-dimethoxy naphthalene (4) a Birch
reduction afforded the 8-methoxy-2-tetralone (5), which was
regioselectively carboxylated with magnesium methylate and
carbon dioxide according to Pelletier et al.,6 and the resulting
acid was esterified with methyl chloroformate in the presence
of triethylamine to give the air-sensitive â-ketoester 6. The
Michael addition of the sodium anion of 6 to acrylonitrile,
followed by carbodemethoxylation to yield the ketonitrile
7, proved to be particularly cumbersome on scale-up, because
it combined a low and unreliable yield with product solutions
which were sensitive to air, temperature, and light. Piperidine
ring closure by hydrogenation over platinium oxide in an
ethanol/chloroform mixture and direct reductive methylation
of the cyclization product with formaldehyde/formic acid
gave a 1:2-ratio of the cis/trans diastereomers, from which
the trans-octahydrobenzo[g]quinoline 8 was separated by
chromatography. The further transformations to the drug
substance 1 employed the resolution of the enantiomers,
bromination, and silylation. The major disadvantage of this
linear synthesis was the low overall yield (<1%) and a huge
waste stream per kilogram of product. Particular weak points
besides the mentioned Michael reaction were the low
regioselectivity of the piperidine ring annellation, the late
resolution of the optical antipodes, and the need for at least
five chromatographic purifications.
Introduction
Synthetic analogues of ergot alkaloids are of interest in
the pharmaceutical and agrochemical industry, because they
exhibit a wide spectrum of physiological activities.1 The
enantiomerically pure JNZ092 (1;2 Figure 1) belongs to the
new octahydrobenzo[g]quinoline class of the ergot analogue
structure family,3,4 which centrally interacts with serotonin-
ergic and R-1-adrenergic receptors without having re-uptake
inhibitory activities for other neurotransmitters. It was chosen
for clinical development because of its potential to act as an
antidepressant and attention-enhancing drug without trig-
gering behavioral or cardiovascular side effects.
In this contribution we describe our experiences with the
successful scale-up of a new synthesis for JNZ092 (1)
* Authors for correspondence. E-mail: markus.baenziger@pharma.novartis.com
and wolfgang.marterer@pharma.novartis.com.
† Novartis Pharma AG, Chemical and Analytical Development.
‡ Novartis Institutes for BioMedical Research, Central Technologies-Prepara-
tions Laboratories.
§ Novartis Institutes for BioMedical Research, Neuroscience.
(1) (a) Berde, B.; Stu¨rmer, E. In Ergot Alkaloids and Related Compounds;
Schield, H. B., Ed.; Springer Press: Berlin/Heidelberg/New York, 1978.
(b) Schardt, F., Miskra, R. B. Ther. Ggw. 1982, 121, 26.
(2) Nozulak J. WO 01/36428, 2001.
In the course of our development activities towards
another ergot project we had established a new large-scale
(3) (a) Nordmann, R.; Petcher, T. J. J. Med. Chem. 1985, 28, 367. (b) Cannon,
J. G.; Amoo, V. E. D.; Long, J. P.; Bhatnagar, R. K.; Flynn, J. R. J. Med.
Chem. 1986, 29, 2529. (c) Tagmatarchis, N.; Thermos, K.; Katerinopoulos
H. E.; J. Med. Chem. 1998, 41, 4165.
(4) Nozulak, J.; Vigouret, J. M.; Jaton, A. L.; Hofmann, A.; Dravid, A. R.;
Weber, H. P.; Kalkman, H. O.; Walkinshaw, M. D. J. Med. Chem. 1992,
35, 480.
(5) Ba¨nziger, M.; Cercus, J.; Stampfer, W.; Sunay, U. Org. Process Res. DeV.
2000, 4, 460.
(6) Pelletier, S. W.; Chappell, R. L.; Parthasarathy, P. C.; Lewin, N. J. Org.
Chem. 1966, 31, 1747.
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10.1021/op034112x CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/05/2003

Figure 1. Octahydrobenzo[g]quinolines 1-3.
Scheme 1. Research synthesis of JNZ092 (1)a
a Reagents and solvents (yield): a) Na, EtOH, H+ (85%); b) Mg, CO2, MeOH (73%); c) ClCO2Me, NEt3, CH2Cl2 (82%); d) CH2dCHCN, toluene, MeOH (40%);
e) LiCl, tetramethylurea (70%); f) PtO2, H2, EtOH, CHCl3; g) HCHO, HCOOH; separation of cis/trans diastereomers (63%); h) (-)-o,o-ditoluolyl-L-tartaric acid,
acetone, diethyl ether (21%); i) Br2, CH2Cl2, CCl4 (95%); j) n-BuLi, TMSCl, THF (60%); k) maleic acid, acetone, diethyl ether (85%).
Scheme 2. Octahydrobenzo[g]quinoline synthesis from ortho-lithiated 1,6-dimethoxynaphthalenea
a Reagents and solvents: a) hexyllithium; b) ethyl-2-cyano-3-ethoxyacrylate; c) 1 M H2SO4; d) H2; Pt/C; e) LiOH; f) HOAc; g) Li /NH3/THF; h) HCl (aq); i)
NaBH4/MeOH; j) MeOH/H2SO4; k) p-TosOH; l) n-propyliodide/K2CO3; m) LDA /TMSCl; n) H3O+.
process to the structurally similar octahydrobenzo[g]quinoline
3.5 As outlined in Scheme 2, the strategy had been to react
an ortho-lithiated 1,6-dimethoxynaphthalene with ethyl-2-
cyano-3-ethoxyacrylate, followed by catalytic hydrogenation
and Birch reduction. This approach was a versatile extension
of a generally applicable concept for the construction of
octahydrobenzo[g]quinolines, initially designed by Hacksell
et al.7 who utilized palladium-catalyzed Heck-reactions of
7-iodo-1,6-dimethoxynaphthalenes and acrylates as the key
assembly step.
We reasoned that an analogous strategy could also be
exploited for the assembly of the octahydrobenzo[g]quinoline
skeleton of 1 starting from 1,7-dimethoxynaphthalene (4),
as outlined in Scheme 3. Careful catalytic hydrogenation of
the adduct 9 to avoid the concurrent reduction of the nitrile
moiety,5 subsequent ester cleavage and decarboxylation
should lead to the stable propionitrile intermediate 12 already
described by the Hacksell group.7 Also the next steps, the
(7) Mellin, C.; Hacksell, U. Tetrahedron 1987, 43, 5443.
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905

Scheme 3. New synthesis of JNZ092 (1)a
a Reagents and solvents: a) n-BuLi, THF; b) ethyl-2-cyano-3-ethoxyacrylate; c) H2, Pt-C; d) NaOH; H2SO4; e) NaCl, dimethylacetamide; f) Na, butanol; h) aq
HCl; i) NaBH4, butanol, acetic acid, water; j) HCO2H, HCHO; k) separation of cis/trans diastereomers; l) (-)-o,o-ditoluolyl-L-tartaric acid; m) NaOH/TBME; n) aq
HBr 48%; NaBrO3, water, acetic acid; o) n-BuLi, THF, TBME, cyclohexane; p) TMSCl; q) maleic acid.
Birch reduction, acidic cyclization, and trans diastereose-
lective reduction to intermediate 15 had literature prece-
dence.7
Thus, the experimental work toward 15 could be dedicated
to optimize the reaction conditions and simplify the workup
procedures. Because of the project’s time constraints it was
planned to follow the medicinal chemistry route for the last
steps towards the drug substance 1 and to postpone the
exploration of stereoselective annelation strategies to a later
development stage.
Assembly of the Octahydrobenzo[g]quinoline Skeleton.
Intermediate 8. We expected the ortho-directed metalation
of 1,7-dimethoxynaphthalene (4) to show a better regiose-
lectivity in the reaction with ethyl-2-cyano-3-ethoxyacrylate
than that of the 1,6-dimethoxynaphthalene, since several
literature examples with structurally related mono- and
dimethoxynaphthalene derivatives suggested an equilibrium
between C6- and C8 lithiation,8 from which preferentially
the adduct 9 should be formed with the bulky Michael
acceptor (Scheme 4).
The yields of 9 from the first experiments, however, were
disappointingly low. One reason was that the ortho-lithiation
of 1,7-dimethoxynaphthalene (4) was incomplete even with
an excess of butyllithium after several hours at -20 °C.
Another crucial variable was the addition of the ethyl-2-
cyano-3-ethoxyacrylate for which a low temperature below
-60 °C was shown to be preferable. The main factor
influencing the yield and quality of the product 9, however,
was found to be the temperature during the addition of the
sulfuric acid for workup. The temperature should be kept
below -25 °C to avoid unproductive side reactions, presum-
ably occurring from the proposed ester enolate anion
intermediate (Scheme 4). In this way the desired adduct 9
could be isolated in up to 83% total yield, which was in
comparison to the same reaction with the 1,6-dimethoxy-
naphthalene5 a yield increase of more than 20%.
The hydrogenation of 9 was done with a 5% platinum on
carbon catalyst at normal pressure.9 The product 10 could
(8) (a) Barnes, R. A.; Bush, W. M. J. Am. Chem. Soc. 1959, 81, 4705. (b)
Shirley, D. A.; Harmon, T. E.; Cheng, C. F. J. Organomet. Chem. 1974,
69, 327. (c) Narasimhan, N. S.; Mali, R. S. Tetrahedron 1975, 31, 1005.
(d) Wilson, J. M.; Cram J. D. J. Org. Chem. 1984, 49, 4930. (e) Johansson,
A. M., Mellin, C.; Hacksell, U. J. Org. Chem. 1986, 51, 5252.
(9) For hydrogenation of similar systems see: (a) Lee, J.; Gauthier, D.; Rivero,
R. A. J. Org. Chem. 1999, 64, 3060. (b) Pollack, M. A. J. Am. Chem. Soc.
1943, 65, 1335.
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Scheme 4. Proposed mechanistic model for the formation of intermediate 9a
a Reagents and conditions: a) n-BuLi, THF, TBME, cyclohexane; b) ethyl-2-cyano-3-ethoxyacrylate; c) 1 M H2SO4.
Scheme 5. “Telescoping” the reaction sequence 12 [f 13 f 14 f 15 ] f 8 to avoid material lossa
a Reagents and conditions: a) sodium, butanol; ca. 95 °C; b) HCl aq, butanol; c) NaBH4, butanol, ethanol, water, acetic acid; d) HCHO 40% aq, HCOOH; e)
separation of diastereomers. (*) Tentative structure assignment for byproducts (1H NMR).
be isolated in 79% yield after crystallization. The only
drawback was the high dilution of the reaction, since the
starting material had a rather low solubility in the organic
solvents used usually in hydrogenation reactions. The car-
bodeethoxylation was performed in two steps. In the first
step the ester 10 was hydrolyzed to the acid 11, which was
isolated in 93% yield. We found that the subsequent
decarboxylation step worked best in the presence of water
and sodium chloride in dimethylacetamide at approximately
130-150 °C, under conditions similar to those recommended
by Krapcho for carbodealkylation reactions,10 to yield the
literature-known propionitrile 127 in 85% yield.
The next key step, the simultaneous reduction of the
methoxynaphthalene moiety and the nitrile function, was
done by carefully adding sodium metal pieces into the
butanol solution of 12 at 90-100 °C. These conditions were
preferred over the protocol by Hacksell,7 who used ethanol
as the solvent and consequently needed a huge excess of
sodium (42 equiv in comparison to 7.5). The reason for this
dramatic improvement simply was the slow rate of sodium
butoxide formation in butanol as compared to fast sodium
ethoxide formation in refluxing ethanol. On larger scale, to
minimize the handling hazards associated with the addition
of reactive sodium at elevated temperatures to a hydrogen-
emitting flammable fluid, the pre-cut sodium cubes were
added in small portions through a nitrogen-inertized double
air-lock system into the reactor. The reaction temperature
of 90-100 °C was found to be particularly important,
because the added sodium pieces immediately melted and
thus were consumed rapidly in the product-forming reduction
steps. At lower temperatures (80-85 °C) the conversion to
13 was hampered, presumably because of the lower surface
of the unmolten metal cubes from which now paradoxically
sodium butoxide formation occurred predominantly. As a
side product, particularly at temperatures above 100 °C, the
1,3-rearranged enol ether was formed (tentative structure
assignment, see Scheme 5), which in the acidic hydrolysis
also led to the cyclic iminium salt 14.
Thus, the use of butanol had a further advantage because
in the hydrolytic workup the oxidation-sensitive enol ether
mixture 13 could be separated with the butanol layer, and
converted directly to the cyclic iminium salt 14 by treatment
with 15% aqueous HCl. When the water and excess of
hydrochloric acid were removed by azeotropic distillation,
it was possible to crystallize the iminium hydrochloride 14
in approximately 65% yield. However, we decided against
this isolation option and subjected the butanol suspension
of 14 (which contained other reducible impurities, tentatively
assigned as “enamines” generated from 14 by 1,3 H-shifts,
see Scheme 5) directly to the sodium borohydride reduc-
tion.11,12 The rational for this was that the cis/trans regiose-
lectivity was not significantly affected, but the yield of 15
increased because the proposed enamine impurities also
produced 15 to some extent. Butanol alone proved not to be
a suitable solvent for the sodium borohydride reduction. We
found that, besides additional acetic acid to enhance the
reduction power of sodium borohydride and to avoid reagent
accumulation, the presence of water and ethanol (or methan-
ol) as solubility mediators was necessary in order to have
(10) (a) Review: Krapcho, A. P. Synthesis 1982, 805. (b) Krapcho, A. P.
Synthesis 1982, 893. (c) Martin, L. J.; Rawson, D. J.; Williams, J. M. J.
Tetrahedron: Asymmetry 1998, 9, 3723.
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907

an acceptable conversion rate and selectivity in the reduction
to the diastereomeric mixture 15. Cis/trans ratios from 1:4
up to 1:9 were achieved, dependent on the amount of water
or ethanol added, which points to the possible involvement
of different borohydride species in the reduction. Again, no
purification was done at this stage and the semisolid 15 after
the hydrolytic workup was directly converted to the corre-
sponding N-methylated cis/trans-mixture 8 following an
optimized protocol for the reductive Leuckart-Wallach
methylation.13 The desired N-methylated trans diastereomer
8 was isolated after a chromatographic purification in 63%
yield (based on 12) and excellent diastereomeric purity
(>98%). This means, that the average yield for these five
“telescoped”14 process steps was >90%. Usually such
telescoping of reaction sequences by circumventing product
isolation or purification is paid for with less robust and less
flexible processes since (a) the probability for unknown
parameter combinations increases with the variability of the
impurity profile entering the subsequent reaction step and
(b) the organizational strain on the pilot plant and analytical
personal increases with the process complexity. In our
example this was justified because selective reactions were
involved, and the problems indeed arose from equilibrating
products hampering the isolation operations.
Resolution of Enantiomers. The resolution of racemic
8 into the enantiomers was done by diastereomeric salt
formation with (-)-o,o-ditoluoyl-L-tartaric acid in ethanol
or acetone, based on the research method. Ditoluoyl-L-tartaric
acid in a 1:1 ratio was the superior resolving agent,15 for
which yields of up to 39% of the free base 16 had been
repeatedly obtained on a multi-ten-gram scale. The first
technical scale-up batch of this method, however, did not
work well because the conditions for the isolation for the
pure diastereomeric salt proved not to be robust at all.
Investigations into the problem revealed that the crystalliza-
tion of the (-)-1:1-ditoluoyl-L-tartrate salt of 16 was
kinetically favored in any suitable solvent (such as acetone,
Figure 2. Chromatographic enantioseparation of 8 on Chiral-
pak-AD. Chromatographic conditions (injection: 10 g of 8
dissolved in 200 mL of mobile phase; mobile phase: hexane/
2-propanol ) 98/2 (v/v); flow rate: 400 [mL/min]; ambient
temp.; UV-detection: 220 nm; CSP: 2 kg; column diameter:
12 cm i.d.; back pressure: 22 bar).
methanol, ethanol, 2-propanol, and their mixtures with
ethers), but then gradually the (+)-diasteromeric salt co-
crystallized to give a (()-salt conglomerate. The tendency
for this detrimental cocrystallization was delayed by the
presence of water and, ironically, also the residual cis
impurity (<1%) in the very pure trans compound 16. The
most important factor, however, was found to be the
temperature for the isolation of the diastereomeric salt. At a
temperature of 37 °C, with stringent observation of the course
of the crystallization with HPLC analysis, finally the
enantiopure (-)-ditoluoyl tartrate salt could be isolated also
on a larger scale and converted to the free base 16 in yields
up to 34% (average 29%).
As a fall-back position a second method for the enantio-
meric resolution was evaluated in our labs using chromato-
graphic separation on Chiralpak AD and demonstrated to
have a considerable potential for future batches. The moder-
ate solubility of 8 in the mobile phase (hexane with only
2% 2-propanol), in combination with a large separation factor
(R) and a good capacity for the above-mentioned chiral
stationary phase (CSP), allowed the easy separation of 8 into
its enantiomers with batch elution chromatography. In a
typical chromatographic run, as shown in Figure 2, 10 g of
8 was separated quantitatively (yield: ∼49%) within 15 min
on a column containing 2 kg of CSP.
To enhance the productivity, the loadability was increased
further using an automated feed injection technique, which
in principle employs the concerted loading of the next sample
while the preceding sample is still separating on the column.
Thus, the rapid separation of 20-g samples had been realized
on lab scale, with only a small decrease of yield. If the
fraction between the collected enantiomers was rechromato-
graphed, the yield was again practically quantitative. Con-
sidering a pilot-plant column with such a repetitive injection
device and a continuous 24-h process, production rates of
0.8 kg of 8/kg of CSP within 1 day should be feasible.
According to our experiences a further increase in productiv-
ity can be achieved, if the process is performed under
simulated moving bed (SMB) conditions. Productivity would
increase by a factor of 2, whereas the real savings will then
arise from the reduced amount of mobile phase, which is
(11) Iminium ions are the proposed intermediates in the reductive amination of
carbonyl compounds (Review: Baxter, E. W.; Reitz, A. B. In Organic
Reactions; Overman, L. E., Ed.; Wiley: New York, 2002; Vol. 59, p 1) for
which reducing reagents such as sodium cyanoborohydride (Borch, R. F.;
Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897), sodium
triacetoxyborohydride (Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;
Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849), or sodium
borohydride have been recommended (e.g., Schellenberg, K. A. J. Org.
Chem. 1963, 28, 3259). Trans-selective reductions of cylic imines have been
reported also with sodium /ethanol (Vierhapper, F. W.; Eliel, E. L. J. Org.
Chem. 1975, 40, 2734).
(12) Hydrogenation over platinum on carbon, palladium on carbon and platinum
oxide was also tested but resulted in an increased amount of the cis
diastereomer, as precedented (e.g., refs 4 and 7).
(13) (a) Li, X.; Schenkel, L. B.; Kozlowski, M. C. Org. Lett. 2000, 2, 875. (b)
Kardos, J.; Blandl, T.; Luyen, N. D.; Doernyei, G.; Ga´cs-Baitz, E.; Simony,
M.; Cash, D. J.; Blasko´, G.; Sza´ntay, C. Eur. J. Med. Chem. 1996, 31, 761.
(c) Kitamura, M.; Lee, D.; Hayashi, S.; Tanaka, S.; Yoshimura, M. J. Org.
Chem. 2002, 67, 8685.
(14) The term “telescoping” has been used before to describe sequential multistep/
multipot processes with shortened or omitted isolation procedures for the
involved intermediates; see, e.g.: Dale, D. J.; Draper, J.; Dunn, P. J.; Hughes,
M. L.; Hussain, F.; Levett, P. C.; Ward, G. B.; Wood, A. S. Org. Process
Res. DeV. 2002, 6, 767.
(15) Other resolving reagents, such as e.g., L-tartaric acid, dibenzoyl-L-tartaric
acid, L-malic acid, (S)-mandelic acid, (1S)-10-camphorsulfonic acid, had
been tested for 8. The results with regard to optical purity, yield, and
crystallization behavior were rated as less favorable as compared to the
diastereomeric salt formation with o,o-ditoluoyl-L-tartaric acid.
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Scheme 6. Reactivity of lithiated 17 towards electrophiles actually or potentially present in the reaction mixture
typically in the order of 10 compared with batch elution
chromatography.
complete conversion, presumably because the low solubility
of the hydrobromide of 17 caused gradual occlusion of the
starting material 16. The reaction can be performed similarly
also in hydrogen bromide/acetic acid solution which enhances
solubility and reactivity. The aqueous bromide/bromate
procedure was scaled up without problems, and the product
base 17 was isolated in up to 92% yield and an excellent
purity (>99%), after treatment of the hydrobromide with
sodium hydroxide and a crystallization.
The final silylation step to 1 was done via rapid bromo-
lithium exchange at temperatures below -70 °C, by addition
of butyllithium in cyclohexane to the THF/TBME solution
of the intermediate 17, followed by quenching the anion with
TMSCl as outlined in Scheme 6.
The lithium anion of 17 was found to be quite stable in
the temperature range between -90 to -50 °C in the solvent
mixture, even when the time until addition of the quench
solution was delayed by several hours. The alkylation
reaction with butyl bromide, generated in the halogen-
lithium exchange reaction, was not of significance under the
reaction conditions, and 19 (Scheme 6) was only formed
slowly if the temperature was raised above -50 °C. The
lithium anion of 17, however, was rather sensitive to
humidity and oxidation. Thus, on large scale the inertization
of the reactor, and particular the careful inertization of the
premixed solution of TMSCl in THF prior to the addition,
was of some importance to avoid the oxidation to 18 as a
side reaction. If 18 was present in the reaction mixture above
1%, an additional chromatographic purification step was
necessary because the final salt formation was hampered by
a strong tendency for crust formation, initiated by the salt
of 18 precipitating on the reactor walls. With the silylated
product free of 18, the hemi-maleinate salt of 1 was isolated
reliably in 78 to 84% yield based on 17.
Bromination and Silylation to 1. The bromination had
been done in the medicinal chemistry route via the slow
addition of an excess of bromine to a solution of the starting
material 16 in a dichloromethane/tetrachloromethane solution
at 0 °C, followed by a reductive workup with aqueous
sodium sulfite and a chromatographic purification.2 Two
equivalents of bromine were necessary because the product
precipitated from the reaction mixture as the insoluble and
rather corrosive hydroperbromide salt (17‚HBr3) which did
not participate in the reaction as a brominating agent. The
objective of our experimental efforts was to replace this
wasteful protocol by the bromide/bromate method in an
acidic aqueous medium,16 in which bromine is generated in
situ (5 Br- + BrO3- + H+ f 3 Br2 + 3 H2O), presumably
via a hypobromous acid transient which also is a strong
brominating reagent.17 Indeed the suspension of 16 in
aqueous hydrobromic acid could be “titrated” by gradually
adding the aqueous sodium bromate solution at 40 °C until
a persistent yellow color of bromine indicated the end of
the reaction. Addition of the bromate solution was preferred,
because alkali bromates generally are strong oxidizing
reagents in acidic medium due to the oxygen-generating
-
disproportion reaction to hypobromous acid (BrO3 + H+
f [HBrO3] f O2 + [HOBr])17 and are able to oxidatively
degrade ethers (such as 17) in autocatalytic reactions.18 With
the inverse bromide/bromate method it was possible to avoid
the bromine excess as well as overbromination and isolate
the crystalline pure hydrobromide salt of 17 simply by
filtration from the reaction mixture. However, it was neces-
sary to add acetic acid to the reaction suspension to achieve
(16) (a) Gilman, H.; Dietrich, J. J. J. Am. Chem. Soc. 1957, 79, 1439. (b)
Fompeydie, D.; Onur, F.; Levillain, P. Bull. Soc. Chim. Fr. 1982, N 1-2,
5-6. (d) Lee, B. S.; Chu, S.; Lee, B. C.; Chi, D. Y.; Choe, Y. S.; Jeong, K.
J.; Jin, C. Bioorg. Med. Chem. Lett. 2000, 10, 1559.
(17) (a) Rothenberg, G.; Beadnall, R. M. H.; McGrady, J. E.; Clark, J. H. J.
Chem. Soc., Perkin Trans. 2 2002, 630. (b) Szalai, I.; Oslonovitch, J.;
Foersterling, H. D. J. Phys. Chem. A 2000, 104, 1495. (c) Kajigaeshi, S.;
Nakagawa, T.; Nagasaki, N.; Yamasaki, H.; Fujisaki, S. Bull. Chem. Soc.
Jpn. 1986, 59, 747. (d) Groweiss, A. Org. Process Res. DeV. 2000, 4, 30.
(18) Metsger, L.; Bittner, S. Tetrahedron 2000, 56, 1905.
Conclusions
The work presented here may be seen as an example of
how the continuous refinement of mechanistic concepts for
the involved reactions can be used to define and optimize
the unit operations of the technical processes. The overall
Vol. 7, No. 6, 2003 / Organic Process Research & Development
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yield of the developed synthesis could be improved by a
factor of 10 in comparison to that of the former research
synthesis. Although not yet exploited for its potential of
stereoselective annelation strategies, this synthesis should be
applicable also to other chiral quinoline systems which, given
a current trend in organic catalysis, could be useful in chiral
catalysis.19
an additional hour at -65 °C and then warmed to -30 °C;
within 0.5 h sulfuric acid (1 M aqueous solution, 64.3 kg)
was added, keeping the temperature below -25 °C. During
the addition the product started to precipitate. The temper-
ature of the reaction mixture was raised to 0 °C and kept for
an additional 30 min. The solids were collected by filtration,
washed with ethyl acetate/hexane, and dried under reduced
pressure at 50 °C to yield intermediate 9 (21.7 kg, 68%).
By extracting the mother liquor with toluene and recrystal-
Experimental Section
1
lization a second crop of 9 (4.8 kg, 15%) was obtained. H
Experimental work is described only for the process,
which was developed and manufactured on multikilogram
scale. The procedures are not fully optimized and reflect the
early development stage of the project. The conditions were
checked for potential hazards by our internal risk analysis
process (DERA)20 and fulfilled the criteria for safe manu-
facture on the scale given.
NMR (CDCl3, 400 MHz): 1.35 (t, J ) 7, 3H), 3.94 (s, 3H),
3.95 (s, 3H), 4.35 (q, J ) 7, 2H), 6.82 (d, J ) 7, 1H), 7.22
(t, J ) 8, 1H), 7.41 (d, J ) 8, 1H), 7.49 (s, 1H), 8.66 (s,
1H), 8.79 (s, 1H). MS: 311. (M+): 296, 268, 241, 208, 180.
2-Cyano-3-(3,5-dimethoxynaphthalen-2-yl)propionic
Acid Ethylester (10). Intermediate 9 (21.63 kg, 69 mol) was
hydrogenated in a mixture of ethanol (202 L) and THF (216
L) over 5% Pt/C (3.26 kg) under normal pressure at 20-30
°C. After the theoretical uptake of 1 equiv of hydrogen (8.5
h) the hydrogenation was stopped, the catalyst was filtered
and washed with ethanol, and the solvent was evaporated
under reduced pressure to a volume of ca. 45 L. This
suspension was gradually cooled to 0 °C, and the solids were
filtered, washed with ethanol (5 L) and hexane (8 L), and
dried under reduced pressure at 45 °C to yield 10 (17.16 kg,
The starting materials, solvents, and reagents were of
technical grade, available in bulk. Butyllithium-cyclohexane
solutions were obtained from Chemetall. Chiralpak-AD used
for the chromatographic separation of the enantiomers
consists of amylose tris(3,5-dimethylphenylcarbamate) coated
on silica gel (20 µm) and has been purchased from Daicel
(Japan). All reactions were carried out under an atmosphere
of nitrogen. The NMR spectra were measured on a Bruker
Avance 400 spectrometer. The chemical shifts are given in
δ (ppm). HPLC purity is given as area normalization.
1,7-Dimethoxynaphthalene (4). To a mixture of 1,7-
dihydroxynaphthalene (9.5 kg, 59.3 mol) and NaOH (5.7 kg,
142.5 mol) in 57.6 kg of water at 20 °C was added dimethyl
sulfate (22.4 kg, 178 mol) within 1.5 h at a rate to maintain
the temperature. This mixture was stirred for another 2 h,
heated to 80 °C for 0.5 h, cooled, and left overnight (16 h)
at 20 °C. Toluene (95 L) and Filteraid (1.5 kg) were added,
and the two-phase system was filtered. After an aqueous
workup (toluene/H2O; NaOH) the toluene layer was evapo-
rated and the crude product 4 distilled by short-path
distillation at 134 °C under reduced pressure of 0.5 mbar,
to yield 8.83 kg (79% yield) of 1,7-dimethoxynaphthalene,
4. 1H NMR (CDCl3, 400 MHz): 3.87 (s, 3H), 3.93 (s, 3H),
6.74 (d, J ) 7, 1H), 7.08 (dd; J ) 2, 9; 1H), 7.18 (t, J ) 8,
1H), 7.29 (d, J ) 8, 1H), 7.46 (d, J ) 2, 1H), 7.62 (d, J )
9, 1H). MS: 188. (M+): 173, 145, 115.
1
79%). HPLC purity: >99%. H NMR (CDCl3, 400 MHz):
1.28 (t, J ) 7, 3H), 3.31 (dd; J ) 13, 9; 1H), 3.49 (dd; J )
13, 7; 1H), 3.96 (s, 3H); 4.01 (s, 3H), 3.96-4.05 (m, 1H).
4.16-4.32 (m, 2H), 6.79 (dd, J ) 8, 1H), 7.26 (t, J ) 8,
1H), 7.32 (d, J ) 9, 1H), 7.52 (s, 1H), 7.62 (s, 1H). MS:
313. (M+): 298, 201, 173.
2-Cyano-3-(3,5-dimethoxynaphthalene-2-yl)propion-
ic Acid (11). To a solution of 10 (11.32 kg, 36 mol) in
ethanol (112 L) was added a solution of NaOH (1.74 kg,
43.5 mol) in H2O (42 L) within 15 min. This mixture was
heated to reflux for 3.5 h, stirred overnight at 25 °C, and
concentrated at approximately 40 °C under reduced pressure
to remove ethanol. The residue was dissolved in an ethyl
acetate (50 L)/toluene (70 L) mixture, and sulfuric acid (50%
aqueous solution, 16 L) was added. The layers were
separated, and the organic phase was concentrated under
reduced pressure to a volume of ca. 45 L. Solids were
isolated by filtration after cooling to 0 °C, washed with ethyl
acetate and hexane, and dried under reduced pressure to give
11 (6.88 kg, 67%. HPLC purity: >95%). From the mother
liquor an additional crop of 11 (2.1 kg, 20%. HPLC purity:
2-Cyano-3-(3,5-dimethoxynaphthalene-2-yl)acrylic Acid
Ethylester (9). To a solution of 1,7-dimethoxynaphthalene
(4, 19.3 kg, 103 mol) in THF (226 L) at -20 °C was added
n-BuLi (20% solution in cyclohexane, 40.4 kg, 126 mol)
within 1 h. The reaction mixture was stirred at 0 °C for
another 3 h and cooled to -70 °C; during 1.25 h a solution
of ethyl-2-cyano-3-ethoxyacrylate (20.1 kg, 119 mol) in THF
(111 L) was added at such a rate that the temperature did
not rise above -65 °C. The reaction mixture was stirred for
1
>97%) was obtained. H NMR (CDCl3, 400 MHz): 3.27
(dd; J ) 14, 8; 1H), 3.53 (dd, J ) 13; 7, 1H), 3.93 (s, 3H),
3.99 (s, 3H), 4.11 (dd, J ) 6; 9; 1H), 6.80 (d, J ) 7, 1H),
7.25 (t, J ) 7, 1H), 7.34 (d, J ) 8, 1H), 7.53 (s, 1H), 7.64
(s, 1H), 9.20-9.80 (br s, 1H). MS: 285. (M+): 270, 241,
201, 173, 158.
3-(3,5-Dimethoxynaphthalene-2-yl)propionitrile (12).
Intermediate 11 (12.57 kg, 44.1 mol) and NaCl (7.46 kg)
were suspended in N,N-dimethylacetamide (25 L) and H2O
(2.75 L). This mixture was slowly heated to 125 °C, where
CO2 evolution started, and was kept at this temperature for
another 2.5 h. [Caution: To avoid a rapid pressure rise the
(19) See, for example: (a) Kita, T.; Georgieva, A.; Hashimoto, Y.; Nakata, T.;
Nagasawa, K. Angew. Chem., Int. Ed. 2002, 41, 2832. (b) McDavid, P.;
Chen, Y.; Deng, L. Angew. Chem., Int. Ed. 2002, 41, 338. (c) C. Schneider,
Angew. Chem., Int. Ed. 2002, 41, 744. (d) Trost, B. M.; Yeh, V. S. C. Angew.
Chem., Int. Ed. 2002, 41, 861.
(20) Spaar, R.; Suter, G. A Simplified Hazard Analysis Scheme for Use in Process
Development. Presented at the 7th International Symposium on Loss
Prevention and Safety Production in the Process Industry, Taormina, Italy,
May 4-8, 1992.
910
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temperature should be raised carefully to the onset of
decarboxylation.] After reaction was complete, the mixture
was cooled to 20 °C and distributed between ethyl acetate
and H2O. The ethyl acetate layer was evaporated under
reduced pressure to a volume of ca. 5 L and cooled to 0 °C.
The solids were collected by filtration, washed with a mixture
of ethyl acetate/hexane (1:1 v/v, 4 L), and dried under
reduced pressure at 40 °C to yield product 12 (8.24 kg, 77%).
From the mother liquor, concentrated to a volume of ca. 1
L, a second crop of 12 (1.5 kg, 14%) was isolated. 1H NMR
(CDCl3, 400 MHz): 2.69 (t, J ) 8, 2H), 3.09 (t, J ) 7, 2H),
3.94 (s, 3H), 3.98 (s, 3H), 6.79 (dd; J ) 7, 1; 1H), 7.24 (t,
J ) 8, 1H), 7.32 (d, J ) 9, 1H), 7.51 (s, 1H), 7.58 (s, 1H).
MS: 241. (M+): 226, 201, 173, 158.
rac-(4aR,10aR)-9-Methoxy-1-methyl-1,2,3,4,4a,5,10,-
10a-octahydrobenzo[g]quinoline (16). (a) Birch/BouVeault
Blanc Reduction of 12. To a solution of 12 (8.2 kg, 34 mol)
in n-butanol (165 L) were carefully added through an
nitrogen-inertized double air-lock system pieces of Na metal
(5.8 kg, 252 mol) at a temperature of 90-95 °C, within
approximately 7 h at such a rate that the preceding portion
had dissolved before a new one was added. [Note: Sodium
bars were pre-cut with adequate precaution into cubes of ca.
2 cm × 2 cm × 2 cm and kept under mineral oil until use.
No efforts were made to remove the mineral oil film before
entering the cubes (3-10 pieces, maximum) into the reac-
tion]. After addition was completed, the mixture was stirred
for an additional 1 h at 95 °C and cooled to 20 °C. H2O (90
L) was slowly added at a rate to maintain the temperature.
The layers were separated. The organic layer was washed
with H2O (35 L), and the combined aqueous phases were
extracted with n-butanol (30 L).
(b) CleaVage of Enol Ether 13 and in Situ Cyclization.
HCl (18% aqueous solution, 14.9 L) was added to the
combined butanol solution of 13, prepared in (a), at such a
rate that the temperature was maintained below 10 °C. The
reaction mixture was stirred for another 2 h at 20 °C, and
then water and residual hydrochloric acid were removed by
refluxing the reaction mixture at a temperature of ca. 50 °C
under reduced pressure at a water trap. At the end of the
distillation the hydrochloride 14 started to crystallize.
(c) Reduction of Cyclic Iminium Hydrochloride 14. To
the suspension of 14 in butanol, prepared in (b), H2O (1.7
L), ethanol (20.7 L), and acetic acid (3.7 L) were added.
Then at 0 °C NaBH4 (2.49 kg, 65.7 mol) was carefully added
within 3.5 h in small portions through a double air-lock
system. [Caution: initial hydrogen evolution is strong.] The
reaction mixture was warmed to 20 °C over an additional
hour, and H2O (48 L) was added at such a rate that the
temperature could be maintained below 20 °C. After stirring
for another 1 h, HCl (18% aqueous solution, 12.4 L) was
added to destroy residual NaBH4 and cleave alkali-persistent
boronic acid adducts of the product amine 15. Then the
mixture was basified again by adding NaOH (30% aqueous
solution, 19.9 L), and the mixture was left overnight. After
an aqueous workup (butanol/H2O), the butanol layer was
evaporated under reduced pressure at 50 °C to give an oily
residue.
(d) Leukart-Wallach N-Methylation. To the evaporation
residue containing 15, prepared in (c), formic acid (5.14 L)
was added. The mixture was heated to 60 °C, and formal-
dehyde (36% aqueous solution, 4.31 L) was added during 1
h. After another 2 h at 75 °C the reaction mixture was cooled
to 10 °C, diluted with H2O (10 L) and 30% NaOH (10 L)
and ethyl acetate. The ethyl acetate layer was separated and
evaporated under reduced pressure to yield a semicrystalline
residue containing a cis/trans diastereomeric mixture of 8.
(e) Chromatographic Separation Of Cis/Trans Diaster-
eomers. The evaporation residue, prepared in (d), was
purified on silica gel (50 kg) with an eluent mixture EtOAc/
MeOH/ NH4OH (1000:10:1 v/v/v), to yield 8 (4.44 kg, HPLC
purity: g95%). From another chromatography run on silica
gel (3.85 kg), separating several contaminated fractions, a
second crop of 8 (0.55 kg) was obtained. The total yield of
1
8 was 4.99 kg (63% based on 12). H NMR (CDCl3, 400
MHz): 1.04-1.22 (m, 1H), 1.66-2.06 (m, 5H), 2.16-2.32
(m, 1H), 2.36-2.58 (m, 5H), 2.76 (dd; J ) 16, 5; 1H), 2.96-
3.08 (m, 1H), 3.27 (dd; J ) 17, 5; 1H), 3.80 (s, 3H), 6.60-
6.70 (m, 2H), 7.04-7.12 (m, 1H). MS: 231. (M+): 216,
115, 110.
(4aR,10aR)-9-Methoxy-1-methyl-1,2,3,4,4a,5,10,10a-oc-
tahydrobenzo[g]quinoline (16). (a) To a solution of inter-
mediate 8 (1.48 kg, 6.4 mol) in EtOH 90% (13.5 L) a solution
of (-)-di-o,o-p-toluoyl tartaric acid in EtOH 90% (64 L)
was added and the mixture heated to 70 °C to obtain a clear
solution. The temperature was lowered to 45 °C, and the
mixture was seeded. Over 60 min the temperature was further
lowered to 37 °C and kept for another 2 h to complete
crystallization. Samples of the solids were taken and checked
by HPLC for enantiopurity. The solids were collected by
filtration via a heated filter (37 °C), washed with ethanol
95% (3 L) of 25 °C, and dried under reduced pressure at 45
°C to yield the ditoluoyl salt of 16 (1.4 kg, 35%) as colorless
crystals. HPLC purity: 98.6%.
(b) To a suspension of the ditoluoyl salt of 16 (3.59 kg,
5.8 mol) in TBME (25 L) and water (23 L) at 25 °C an
aqueous sodium hydroxide solution (30%, 1.6 L) was slowly
added to adjust to pH 12-13. The layers were separated.
The water layer was extracted with TBME (total 30 L), and
the combined organic layers were washed with water (16
L). The solvent was removed under reduced pressure at 50
°C to yield 16 (1.34 kg, 99%) as a colorless crystalline
residue. (HPLC chemical purity: >98%, enantiomeric
purity: >98%).
(4aR,10aR)-6-Bromo-9-methoxy-1-methyl-1,2,3,4,4a,5,-
10,10a-octahydrobenzo[g]quinoline (17). To a solution of
16 (1.34 kg, 5.79 mol) in H2O (13.4 L) and acetic acid (10
L) was added HBr (48% aqueous solution, 1.7 L, 15.1 mol).
At 40 °C a solution of sodium bromate (0.37 kg, 2.4 mol)
in H2O (7.0 L) was added within 50 min at a rate to maintain
the temperature. The reaction suspension was stirred for
another 1 h at 40 °C, diluted with H2O (9.7 L), and cooled
to 25 °C. A solution of sodium thiosulfate (135 g) in H2O
(2.7 L) was added to destroy the excess of brominating
reagent. The suspension was cooled to 0 °C, and the solids
(hydrobromide of 17) were collected by filtration and washed
Vol. 7, No. 6, 2003 / Organic Process Research & Development
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911

with H2O (6 L). In the aqueous workup (TBME (20 L)/H2O
(12 L)/NaOH (30% aqueous solution, 1.8 L) the free base
17 was liberated at a pH 13-14. The organic layer was
separated and concentrated to 1 L and after adding hexane
(0.6 L) was gradually cooled to 0 °C. The solids were
collected by filtration, washed with hexane (1 L), and dried
at 45 °C under reduced pressure to yield 1.64 kg of product
17 (92%; HPLC chemical purity: >99%, enantiomeric
the product was eluted with hexane/TBME mixtures (3:1 and
2:1 v/v; detection UV 254 nm). The product fractions
containing pure 1 were concentrated under reduced pressure
at 40 °C to give 1 (0.96 kg, 85% recovery) as a colorless
solid evaporation residue.
(4aR,10aR)-6-Hydroxy-9-methoxy-1-methyl-1,2,3,4,-
1
4a,5,10,10a-octahydrobenzo[g]quinoline (18): H NMR
CDCl3, 400 MHz: 1.16 (m, 1H), 1.60-2.00 (series of m,
5H), 2.15-2.28 (m, 2H), 2.35 (dd, 1H), 2.43 (s, 3H), 2.90
(dd, 1H), 3.00 (br d, 1 H), 3.32 (dd, 1H), 3.78 (s, 3H), 6.59
(AB, 2H). MS: 247. (M+): 232, 150, 97, 82, 77.)
1
purity: >99%). H NMR (CDCl3, 400 MHz): 1.03-1.16
(m, 1H), 1.60-1.95 (m, 5H), 2.16-2.28 (m, 1H), 2.32-
2.44 (m, 4H), 2.86-3.02 (m, 2H), 3.22 (dd; J ) 17, 5; 1H),
6.50 (d, J ) 9, 1H), 7.27 (d, J ) 9, 1H). MS: 311. (M+):
309. (M+): 296, 294, 230, 173, 158.
(c) Hemi-maleinate formation. Crude 1 (0.87 g, 2.87 mol)
was dissolved in TBME (total 23.5 L), treated with activated
carbon (0.1 kg), and filtered at 36 °C to a solution of maleic
acid (0.35 kg, 3.0 mol) in acetone (1.34 kg). After seeding,
the product 1 started gradually to crystallize as the hemi-
maleinate salt. The suspension was cooled to 0 °C over a
period of 7 h and kept for another 1 h at this temperature.
The solids were collected by filtration, washed with TBME
(2 L), and dried at 50 °C to yield 1 as the hemi-maleinate
salt (1.0 kg, 83%. HPLC chemical purity: >99.5%, enan-
(4aR,10aR)-9-Methoxy-1-methyl-6-trimethylsilanyl-
1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline Hemimal-
einate (1). (a) Silylation. To the solution of intermediate 17
(1.3 kg, 4.2 mol) in THF (13 L) and TBME (13 L) at -75
°C was added n-BuLi (20% solution in cyclohexane, 2.04
kg, 6.4 mol) at a rate such that the temperature did not rise
above -70 °C. After rinsing with TBME (0.5-1 L) and
stirring for another 15 min, TMSCl (0.96 kg, 8.8 mol) was
added within 20 min at a rate such that the temperature did
not rise above -70 °C. After the addition was complete,
the reaction mixture was warmed to 0 °C, and NaOH (2 M
aqueous solution, 1.3 L) was added at a temperature below
10 °C, followed by H2O (45 L). The mixture was warmed
to ambient temperature, and the layers were separated. The
aqueous layer was extracted with TBME, and the combined
organic layers were washed with water. The organic phase
was concentrated by distillation under reduced pressure at
40 °C to give crude 1 (1.13 kg, 89%; MS: 304 (M + H)) as
a slightly red-colored solid.
1
tiomeric purity: >99.9%). H NMR (CDCl3, 400 MHz):
0.21 (s, 9H), 1.20 -1.36 (m, 1H), 1.80-1.90 (m, 1H), 1.98-
2.07 (m, 1H), 2.16-2.28 (m, 2H), 2.46-2.56 (m, 1H), 2.72-
2.90 (m, 6H), 3.02 (dd; J ) 17, 5; 1H), 3.28-3.38 (m, 1H),
3.56-3.68 (m, 1H), 3.74 (s, 3H), 6.22 (s, 2H), 6.62 (d, J )
8, 1H), 7.26 (d, J ) 8, 1H), 12.14 (br s, 1H).
Acknowledgment
The skillful work of our technical staff (A. Ehrsam, P.
Heusser, K. Jenni, P. Schmid, and H. Vonarburg) is gratefully
acknowledged. Drs. Ch. Heuberger and J. Wiss are thanked
for thermal stability measurements, and the pilot plant team,
for the realization of the up-scaling.
(b) Chromatography. The batch described under (a)
contained oxidation product 18 in an amount higher than
1% (HPLC) and therefore was dissolved in 1.4 L hexanes
for chromatography. The hexane solution was filtered at
approximately 50 bar over a pad of silica gel (25 kg,
preconditioned with hexane/ triethylamine (20:1 w/w)), and
Received for review August 6, 2003.
OP034112X
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