The development of a new manufacturing route to the novel anticonvulsant, SB-406725A

Article abstract of DOI:10.1021/op9002054

The development of an efficient manufacturing route to 3-acetyl - N - (5,8-dichloro-1,2,3,4-tetrahydro-7-isoquinolinyl)-4-(1-methyl- ethoxy)-benzamide hydrochloride SB-406725A (1) is described. The synthesis begins with dichlorination of isoquinoline, followed by nitration using nitronium tetrafluoroborate in sulpholane. Nitroisoquinoline (12) was hydrogenated under pressure using Pt/C. The resultant tetrahydroisoquinoline (13) was selectively coupled with benzoate side chain (15) under base-promoted conditions using sodium hexamethyldisilazane to yield the parent molecule SB-406725 (16). SB-406725 was then converted to the HCl salt SB-406725A (1). This process has been successfully demonstrated on a pilot-plant scale to prepare ～30 kg of SB-406725A (1).

Full text of DOI:10.1021/op9002054

Organic Process Research & Development 2010, 14, 108–113
The Development of a New Manufacturing Route to the Novel Anticonvulsant,
SB-406725A
Matthew D. Walker,* Benjamin I. Andrews, Andrew J. Burton, Luke D. Humphreys, Gary Kelly, Mark B. Schilling, and
Peter W. Scott
Synthetic Chemistry, GlaxoSmithKline Pharmaceuticals, Medicines Research Centre, Gunnels Wood Road,
SteVenage SG1 2NY, U.K.
Abstract:
The development of an efficient manufacturing route to 3-acetyl-
N-(5,8-dichloro-1,2,3,4-tetrahydro-7-isoquinolinyl)-4-(1-methyl-
ethoxy)-benzamide hydrochloride SB-406725A (1) is described.
The synthesis begins with dichlorination of isoquinoline, followed
by nitration using nitronium tetrafluoroborate in sulpholane.
Nitroisoquinoline (12) was hydrogenated under pressure using Pt/
Figure 1. SB-406725A (1).
C. The resultant tetrahydroisoquinoline (13) was selectively
2 via trifluoroacetylation, followed by in situ Pictet-Spengler
coupled with benzoate side chain (15) under base-promoted
conditions using sodium hexamethyldisilazane to yield the parent
molecule SB-406725 (16). SB-406725 was then converted to the
HCl salt SB-406725A (1). This process has been successfully
demonstrated on a pilot-plant scale to prepare ∼30 kg of SB-
406725A (1).
cyclisation to give tetrahydroisoquinoline 3 in 81% overall yield.
The trifluoroacetyl group was required to make the intermediate
N-acyliminium species sufficiently electrophilic for attack by
the electron-deficient aromatic nucleus.2 This was followed by
introduction of the chlorine in the 5-position of tetrahydroiso-
quinoline 3 using a two-step procedure involving selective
electrophilic iodination of 3 followed by halogen metathesis
from iodine to chlorine to give 5-chlorotetrahydroisoquinoline
5 in 77% overall yield.3,4 Again, this two-step procedure was
required due to the electron-deficient nature of the aromatic ring.
Reduction of the nitro group in tetrahydroisoquinoline 5 was
achieved in 84% yield via an iron-based dissolving metal
reduction. The resultant aniline 6 was then chlorinated in 38%
yield using NCS to give the required dichloroaniline fragment
7.5 The yield for this reaction was highly variable (between
30% and 55%), due to the generation of highly coloured polar
decomposition products which inhibited crystallisation of the
desired product.
For route A, dichloroaniline 7 was then carbonylatively
coupled with aryl bromide 8 in DMF under 0.2 barg of carbon
monoxide at ∼100 °C using bis(triphenylphosphine)palla-
dium(II) chloride as the precatalyst to give amide 9 in 75%
yield.6 This reaction was also somewhat irreproducible, possibly
due to a lack of stability in the palladium carbonyl catalyst.7
Final stage deprotection of the trifluoroacetyl group of amide
9, followed by hydrochloride salt formation gave the product
SB-406725A 1 in 85% yield (∼13% overall theory yield from
phenethylamine 2).
Introduction
SB-406725A 1 (Figure 1) was developed for use as a novel
anticonvulsant for the treatment of neuropathic pain, migraine,
and epilepsy.1
Initial toxicology and clinical studies were supplied via routes
A and B starting from 4-nitrophenethylamine hydrochloride 2
(Scheme 1). Neither route A nor route B was suitable for use
as the final route of manufacture as they did not meet our
development criteria (greater than six steps) or the target for
the cost of goods. In addition, there were a number of issues
with routes A and B, including protection and deprotection of
the trifluoroacetyl group, a low-yielding electrophilic chlorina-
tion and, in the case of route A, use of a carbonylative amidation
for a quality critical coupling. We report here the identification
and development of a new concise route that addresses these
problems to produce the target molecule in improved yield.
Results and Discussion
Initial Supply Route to SB-406725A (1). The initial
syntheses of SB-406725A 1 (Scheme 1) both proceeded through
the common dichloroaniline 7. Synthesis of dichloroaniline 7
was achieved starting from 4-nitrophenethylamine hydrochloride
For route B, dichloroaniline 7 was coupled with the acid
chloride of benzoic acid 10 to give amide 9 in 85% yield. We
* To whom correspondence should be addressed. Telephone: 01438 768179.
Fax: 01438 764242. E-mail: matthew.d.walker@gsk.com.
(2) Stokker, G. E. Tetrahedron Lett. 1996, 37, 5453–5456.
(3) Kraszkiewicz, L.; Sosnowski, M.; Skulski, L. Tetrahedron 2004, 60,
9113–9119.
(1) (a) Harling, J. D.; Heer, J. P.; Thompson, M. Substituted isoquinoline
derivatives and their use as anticonvulsivants. U.S. Patent 6,492,378,
2002. (b) Coulton, S.; Porter, R. A. Substituted isoquinoline derivatives
and their use as anticonvulsants. U.S. Patent 6,248,754, 2001. (c) Xue,
C.-B.; Zheng, C.; Cao, G.; Feng, H.; Xia, M.; Anand, R.; Glenn, J.;
Metcalf, B. W. 3-(4-Heteroarylcyclohexylamino)cyclopentanecarbo-
xamides as modulators of chemokine receptors. U.S. Patent 7,307,086,
2007.
(4) Bacon, R. G. R.; Hill, H. A. O. J. Chem. Soc. 1964, 1097–1107.
(5) Neale, R. S.; Schepers, R. G.; Walsh, M. R. J. Org. Chem. 1964, 29,
3390–3393.
(6) Schoenberg, A.; Heck, R. F. J. Org. Chem. 1974, 39, 3327–3331.
(7) For a recent review about palladium carbonyl complexes see:
Stromnova, T. A.; Moiseev, I. I. Russ. Chem. ReV. 1998, 67, 485–
514.
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10.1021/op9002054 CCC: $40.75  2010 American Chemical Society
Published on Web 11/16/2009

Scheme 1. Route A to SB-406725A (1)
Scheme 2. Route B to SB-406725A (1)
Scheme 3. Alternative retrosynthetic analysis of SB-406725A (1)
found this coupling reaction to be much more reproducible,
despite some evidence of overacylation of the product in the
crude reaction mixture due to the high reactivity of the
intermediate acid chloride. Completion of the final stage
deprotection and salt formation gave the product SB-406725A
1 in 85% yield (∼12% overall yield from phenethylamine 2).
Identification of a New Route to SB-406725A (1) via 5,8-
Dichloroisoquinoline (11). In light of the difficulty experienced
in carrying out the Pictet-Spengler cyclisation with these
electron-deficient and sterically hindered substrates, an alterna-
tive synthetic strategy was devised that relied on the selective
functionalisation of isoquinoline (Scheme 3).8 In the forward
sense, synthesis of the known isoquinoline 11 followed by
nitration and reduction would yield tetrahydroisoquinoline 13
as the key coupling partner. It was then envisaged that selective
acylation of this aniline 7 with a suitable benzoyl derivative
(such as benzoic acid 10) would complete the synthesis of SB-
406725A 1.
Development of the Synthesis of 5,8-Dichloroisoquino-
line(11). To begin our synthesis of SB-406725A 1 a scalable
method for the synthesis of 5,8-dichloroisoquinoline 11 was
required. A review of the literature showed two potential routes;
Pommerantz-Fritsch reaction of 2,5-dichlorobenzaldehyde and
aminoacetaldehyde dimethylacetal, or dichlorination of iso-
quinoline using molecular chlorine and aluminium trichloride.9,10
Our initial attempts to synthesise 5,8-dichloroisoquinoline
11 were carried out on up to 20 g scale via the Pommerantz-
Fritsch reaction. In our hands this required the intermediate
imine to be preformed and added neat to 98% sulphuric acid
at ∼150 °C. The product was obtained in low yield (<30%)
and could not be isolated sufficiently pure for further use without
column chromatography. We were prompted by the report of
Brown and Gouliaev on the regioselective dibromination of
isoquinoline 14 to evaluate the alternative procedure using
isoquinoline as the starting material and electrophilic chlorinat-
ing agents such as NCS or N,N′-dichlorodimethylhydantoin
(DCDMH).11 After screening a range of electrophilic chlorinat-
ing conditions we were pleased to be able to isolate the product
(8) Our initial strategy towards the synthesis of SB-406725 1 was to
synthesise the desired aniline 7 via a Pictet-Spengler reaction in an
analogous system with both chlorines already present in the starting
nitrophenethylamine. Disappointingly, exposure of 2,5-dichloro-4-
nitrophenethylamine to our standard Pictet-Spengler conditions gave
only recovered starting material. We attributed this lack of reactivity
to the combination of steric and electronic effects further deactivating
the aromatic nucleus, preventing the cyclisation onto the N-acylimin-
ium ion.
(9) Bondinell, W. E.; Chapin, F. W.; Girard, G. R.; Kaiser, C.; Krog,
A. J.; Pavloff, A. M.; Schwartz, M. S.; Silvestri, J. S.; Vaidya, P. D.;
Lam, B. L.; Wellman, G. R.; Pendleton, R. G. J. Med. Chem. 1980,
23, 506–511.
(10) Gordon, M.; Pearson, D. E. J. Org. Chem. 1964, 29, 329–332.
(11) Brown, W. D.; Gouliaev, A. H. Synthesis 2002, 83–86.
Vol. 14, No. 1, 2010 / Organic Process Research & Development
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109

Table 1. Classical nitration of 5,8-dichloroisoquinoline (11)
We next turned our attention to alternative nitrating reagents,
in particular, nitronium salts as a neutral source of the nitronium
ion.12 A range of nitronium salts and conditions was investigated
(Table 2).
Solvent studies suggested that sulpholane was essential in
order for the reaction to occur, and although dichloromethane
could be used as a co-solvent, other solvents were either
incompatible or led to no reaction.
using different co-acids
entry
conditionsa
co-acid pKa
result
1
2
3
4
f. HNO3, H3PO4, 18 h
f. HNO3, TFA, 18 h
f. HNO3, 18 h
2.1
–0.3
–1.3
–2.6
recovered SM
recovered SM
recovered SM
11% product,
86% SMb
f. HNO3, MsOH, 18 h
5
6
7
f. HNO3, H2SO4, 48 h
90% HNO3, H2SO4, 48 h
69% HNO3, H2SO4, 48 h
–3.0
–3.0
–3.0
29% productc
25% productc
15% product,
22% SMc
Interestingly, the nature of the nitronium counterion appears
to affect the selectivity observed: upon changing the counterion
from tetrafluoroborate to trifluoroacetate (entries 1-4), the
percentage of the 4-nitro isomer increases. This suggests a link
between the nitronium counterion nucleophilicity and the
regioselectivity of nitration.14 We ultimately elected to carry
out the nitration using nitronium tetrafluoroborate in sulpholane
(entry 1), taking into account a combination of yield, selectivity,
and the cost of trifluoromethanesulphonic acid and trifluo-
romethanesulphonic anhydride. We were again able to transfer
production of 7-nitro-5,8-dichloroisoquinoline 12 to a third
party, where the product was isolated in 76% yield on a 40 kg
scale.
Development of the Reduction of 7-Nitro-5,8-dichlor-
oisoquinoline (12). A selective reduction of both the nitro group
and the isoquinoline ring in the presence of the aryl chloride in
nitroisoquinoline 12 was then sought. Initial screening work
demonstrated that the reduction of nitroisoquinoline 12 to amino
tetrahydroisoquinoline 13 was possible with 50 psi hydrogen
pressure using PtO2 in either NMP or methanol using 98%
sulphuric acid as co-catalyst. These reactions were somewhat
problematic, however, due to the rate being limited by the poor
solubility of intermediates generated during the reduction, in
particular, that of the corresponding amino isoquinoline.15 In
addition, it was found that the isolated product from this initial
method was a variable nonstoichiometric mixture of the sulphate
and methylsulphate salts which was highly undesirable due to
the potentially toxic nature of these counterions.
A screen of alternative solvents, catalysts, and acid co-
catalysts led us to carry out the reduction using Degussa Pt/C
F105 R/W as the catalyst in methanol with acetic acid as a
co-catalyst with higher pKa. This not only gave the desired 13
as a well-defined acetic acid salt but also resulted in significantly
less dechlorination in solution compared to the use of 98%
sulphuric acid (typically <1% a/a with acetic acid cf. ∼5% a/a
with sulphuric acid in solution by HPLC).
An experimental design study based on these revised reaction
conditions showed that the nitro reduction and the isoquinoline
reduction had differing critical parameters. For the reduction
of the nitro group, catalyst loading was the major rate driver
8
f. HNO3, TfOH, 6d
–14.0
57% productc
a All reactions performed at RT. b Percentage a/a determined by HPLC.
c Isolated yield.
in 98% yield by treating isoquinoline 14 with DCDMH in 98%
sulphuric acid. We were able to use this method to prepare
sufficient material for lab-scale development of the remainder
of this route. We were then able to transfer production of 5,8-
dichloroisoquinoline 11 via electrophilic chlorination to a third
party, who supplied us with 220 kg of 11 prepared by this route.
Development of the Nitration of 5,8-Dichloroisoquinoline
(11). Literature precedent for the selectivity of electrophilic
substitution in 5,8-disubstituted isoquinoline systems suggested
that substitution in the 7-position is favored;10 we were therefore
keen to ascertain whether this would be the case in the nitration
of 11 to give the corresponding 7-nitro derivative 12.
Initial efforts towards the nitration of 5,8-dichloroisoquino-
line 11 using potassium nitrate and 98% sulphuric acid failed,
giving only recovered starting material. Use of fuming nitric
acid and 98% sulphuric acid gave complete consumption of
the starting material after 18 h and the desired product in an
isolated yield of 29%. The mass balance remained in the
aqueous phase as polar aromatic decomposition products, from
which pyridine-3,4-dicarboxylic acid was identified, resulting
from oxidative cleavage of the starting material. An experi-
mental design study was performed in an attempt to optimise
these conditions, but unfortunately, solution yields were uni-
formly low (<30% yield).
We therefore decided to investigate a wider range of classical
acid catalysed nitration conditions to ascertain whether nitration
could be achieved in preference to oxidation (Table 1).12
It was interesting to note that only reactions with sulphonic
acids gave significant conversions (entries 4-8), demonstrating
that effective nitration depends on the ability of the co-acid to
both protonate and dehydrate the nitric acid. The oxidising
power of nitric acid is related to its concentration, so the strength
of the nitric acid was varied in an effort to minimise competing
oxidation (entries 5-7). However, no advantage was gained
by using less concentrated nitric acid. The best isolated yield
attained was 57% using triflic acid as co-acid, albeit over a
prolonged reaction period.
(13) Elsenbaumer, R. L. J. Org. Chem. 1988, 53, 437–439.
(14) These observations led us to speculate that the mechanism of the
nitration proceeds via initial N-nitration to give the N-nitro isoquino-
linium intermediate. This may then revert to starting material or react
to give either the desired isoquinoline 11 or the undesired 4-nitro
isomer. It is not known whether conversion of the N-nitro isoquino-
linium intermediate to the product occurs by nitration with further
NO2+, transfer nitration from a second N-nitro isoquinolinium species,
or intramolecular rearrangement.
(15) Reduction was observed to occur via a poorly soluble aminoisoquino-
line intermediate. Carrying out the reaction at an elevated temperature
was required to prevent precipitation of this material onto the platinum
catalyst, which would result in catalyst deactivation.
(12) (a) Olah, G.; Kuhn, S.; Mlinko´, A. J. Chem. Soc. 1956, 4257–4258.
(b) Woolf, A. A.; Emele´us, H. J. J. Chem. Soc. 1950, 1050–1052. (c)
Goddard, D. R.; Hughes, E. D.; Ingold, C. K. J. Chem. Soc. 1950,
2559–2575. (d) Olah, G. A.; Orlinkov, A.; Oxyzoglou, A. B.; Surya
Prakash, G. K. J. Org. Chem. 1995, 60, 7348–7350. (e) Olah, G. A.;
Rasul, G.; Aniszfeld, R.; Surya Prakash, G. K. J. Am. Chem. Soc.
1992, 114, 5608–5609.
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Table 2. Nitration of 5,8-dichloroisoquinoline (11) using different nitronium salts
entry
conditionsa
productb (%)
4-NO2 isomer (%)
1
2
3
2.25 equiv NO2BF4, sulpholane, 80 °C, 3 h
1.5 equiv NO2PF6, sulpholane, 50 °C, 18 h
4 equiv NO2OTf (nBu4N·NO3 and Tf2O), DCM/sulpholane,
40 °C, 5dc
70
60
75
-
5
9
4
2 equiv NO2 ·2CCF3 (nBu4N·NO3 and TFAA), CH2Cl2/
sulpholane, 40 °C, 18 h
-
38
d
5
6
7
8
1.8 equiv NO2BF4 , 2 equiv TfOH, sulpholane, 80 °C, 2 h
93
36
-
-
-
-
d
1.8 equiv NO2BF4 , 2 equiv MsOH, sulpholane, 80 °C, 2 h
d
1.8 equiv NO2BF4 , 2 equiv ClSO3H, sulpholane, 80 °C, 2 h
no reaction
83
2 equiv NO2OTf (nBu4N·NO3 and Tf2O), 2 equiv TfOH, DCM/
sulpholane, 40 °C, 24 h
a Reactions carried out with a 5 vol:5 vol ratio of sulpholane/DCM, where appropriate. b Percentage a/a determined by HPLC. c Reagents added portionwise over the
course of the reaction. d 1 equiv of NO2BF4 after assaying the reagent and correcting for the amount of NO+ present.13
followed by pressure, whereas for the isoquinoline reduction,
temperature was the major rate driver followed by the stoichi-
ometry of the acetic acid co-catalyst. In addition, reaction
calorimetry showed that the reduction of the nitro group during
the early phase of the reaction is strongly exothermic, accounting
for the majority of the total heat evolved in the reaction.
Accordingly, the process was conducted using 5% Pt/C (0.2
wt %) in methanol and acetic acid at 3.5 barg pressure starting
at 20 °C. After the initial exothermic phase, the reaction was
heated to 50 °C to complete the reduction of the isoquinoline
functionality.
The free base of 13 was established as the preferred isolated
version for the downstream chemistry. Attempts to isolate the
free base directly by neutralisation, after catalyst filtration,
generally gave poor-quality material and low recoveries of the
desired product. Improvement in the quality of free base was
achieved when the intermediate acetic acid salt was isolated as
a wet cake and then neutralised prior to crystallisation from
aqueous THF. A consistent level of residual platinum in the
product (∼100 ppm) was observed using this process, which
could be tolerated in the downstream chemistry. We were able
to carry out this process on a 10 kg scale, giving the product in
55% isolated yield.
Development of the Coupling of 7-Amino-5,8-dichlo-
rotetrahydroisoquinoline (13) with a Benzoate Side Chain.
Having developed a concise synthesis of amino tetrahydroiso-
quinoline 13 we were intrigued by the possibility of coupling
this directly to a suitably functionalised side chain without
protecting the secondary amine. Selective protonation of 13 with
HCl and attempted amidation with benzoic acid 10 using thionyl
chloride as the activating agent gave rise to a mixture of
products arising from acylation of both the aniline and secondary
amine centres of amino tetrahydroisoquinoline 13, indicating
that the protonation did not prevent reaction at the secondary
amine centre for this substrate.16
secondary amine functions by taking advantage of their relative
acidities. On the basis of the reported use of sodium hexam-
ethyldisilazane (NaHMDS) to generate aryl anilides and that
NaHMDS has a pKa of 26 (in THF), we considered it should
be ideally placed to deprotonate anilines (pKa ≈ 25-30) in the
presence of alkyl amines (pKa ≈ 35).19 Our initial experiments
showed that, as anticipated, the aniline group of 13 was shown
to be deprotonated with NaHMDS and then to react with methyl
benzoate 15 to give the required amide 16 as the free base.
Following this promising result, a range of alternative bases
was screened (BuLi, KHMDS, LiHMDS, and NaOMe). The
best reaction profile was achieved with NaHMDS in THF, other
conditions giving either no reaction or decomposition of the
starting materials. After studying the reaction parameters via
an experimental design study we found that the optimum
reaction conditions employed a small excess (1.1-1.3 equiv)
of methyl benzoate side chain 15 and 5-6 equiv of NaHMDS
at 0 °C. The process was observed to tolerate both the methyl
ketone and aryl halide functionalities and was carried out on a
10 kg scale, giving the product in 83% isolated yield.20
We were then able to adapt the isolation from acidic aqueous
propan-1-ol used in routes A and B, in order to complete the
required conversion of freebase 16 to HCl salt 1. Dissolution
and clarification of the free base in THF, prior to solvent
exchange into propan-1-ol and acidification with a mixture of
water and 36% w/w hydrochloric acid, was shown to give the
desired product with the correct form and required purity in
88% yield on an 11 kg scale (Scheme 4).
Summary
In conclusion, a robust, efficient, and scalable process has
been developed suitable for the synthesis SB-406725, 1, in 30%
(18) The production of the methyl benzoate side chain 15 was carried out
externally starting from 4-hydroxybenzoic acid. Ortho-acylation under
Fries conditions, followed by esterification with methanol and finally
alkylation using isopropyl bromide provided the desired methyl
benzoate side chain 15.
(19) (a) Fraser, R. R.; Mansour, T. S.; Savard, S. J. Org. Chem. 1985, 50,
3232–3234. (b) In addition, NaHMDS is readily soluble in a wide
range of organic solvents, is not prone to single-electron transfer side
reactions, and is less pyrophoric than many other organometallic
reagents, making it more suitable for use on scale.
At this point we were prompted by the report of Wang et
al. to attempt the reaction of 13 with methyl benzoate 15 under
base-promoted conditions.17,18 We hypothesised that it would
be possible to obtain chemoselectivity between the aniline and
(16) Oganesyan, A.; Cruz, I. A.; Amador, R. B.; Sorto, N. A.; Lozano, J.;
Godinez, C. E.; Anguiano, J.; Pace, H.; Sabih, G.; Gutierrez, C. G.
Org. Lett. 2007, 9, 4967–4970.
(20) Only a trace amount (<1% a/a by HPLC) of the bis-amide species
was observed in these batches which was readily removed in the
subsequent hydrochloride salt formation step.
(17) Wang, J.; Rosingana, M.; Discordia, R. P.; Soundararajan, N.;
Polniaszek, R. Synlett 2001, 9, 1485–1487.
Vol. 14, No. 1, 2010 / Organic Process Research & Development
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111

Scheme 4. Route C synthesis of SB-406725 (1)
overall yield.21 This approach utilises regioselective dichlori-
nation and nitration of isoquinoline followed by chemoselective
reduction and then selective acylation of amino tetrahydroiso-
quinoline 13 to form the desired product 1 after salt formation.
This more concise and atom-efficient route uses a readily
available starting material, avoids the protection and deprotec-
tion steps required in previous routes, and also has a more robust
final coupling stage.
was added in portions to sulpholane (3.5 L) at 50 °C. The
reaction mixture was then heated to 60 °C and the reaction
mixture stirred for 18 h. The reaction mixture was then cooled
to 20 °C and quenched by the addition of 1.5 M sodium
hydroxide solution (6.6 L, 9.90 mol) over 1 h, maintaining the
internal temperature below 40 °C during the quenching. The
reaction mixture was then filtered and washed with water (800
mL) followed by ethanol (2 × 800 mL). The wet cake was
then added to THF (6.5 L) and heated to 60 °C and then cooled
to 40 °C over 40 min and then to 0 °C over 150 min. The
resultant slurry was then filtered and washed with ethanol (2
× 500 mL) and dried to give a pale-brown solid (468 g, 76%
Experimental Section
5,8-Dichloroisoquinoline (11) from Isoquinoline (14).
Isoquinoline 14 (400 g, 3.09 mol) was added over 15 min to
98% sulphuric acid (2.4 L) precooled to 2 °C (the maximum
temperature during the addition was 21 °C). 1,3-Dichloro-5,5-
dimethylhydantoin (1200 g, 6.09 mol) was then added in
portions over 30 min, while the temperature was allowed to
gradually increase from 10 to 25 °C. The reaction mixture was
then heated to 55 °C and stirred for 18 h. The reaction mixture
was cooled to ambient temperature and quenched into water
(19.2 L) at 5 °C. Thereafter, 50% w/w sodium hydroxide
solution (900 g, 11.25 mol) was added over 60 min. The
quenched mixture was extracted with TBME (3.2 L). The
organic phase was washed with saturated aqueous sodium
hydrogen carbonate (800 mL) and dried (MgSO4). Evaporation
gave a pale-brown solid (601 g, 98% yield): mp 116-118 °C
(lit. 115-116 °C). 1H NMR (400 MHz, CDCl3) δ 9.64 (s, 1H),
8.71 (d, J ) 5.9 Hz, 1H), 7.97 (d, J ) 5.9 Hz, 1H), 7.63 (d, J
) 8.1 Hz, 1H), 7.51 (d, J ) 8.1 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 149.7 (CH), 145.1 (CH), 134.7 (C), 131.4 (C), 130.0
(CH), 130.0 (C), 127.3 (CH), 126.2 (C), 116.7 (CH). LRMS
(ES +VE): m/z 198, 239 (M+ + H, M+ + MeCN).
1
yield): mp 186-188 °C. H NMR (400 MHz, d6-DMSO) δ
9.83 (s, 1H), 8.98 (d, J ) 5.9 Hz, 1H), 8.66 (s, 1H), 8.18 (d, J
) 5.9 Hz, 1H). 13C NMR (100 MHz, d6-DMSO) δ 150.6 (CH),
147.7 (CH), 145.6 (C), 135.1 (C), 130.6 (C), 125.2 (CH), 125.1
(C), 123.9 (C), 116.5 (CH). MS (ES +VE): m/z 243, 284 (M+
+ H, M+ + MeCN).
7-Amino-5,8-dichlorotetrahydroisoquinoline (13) from
7-Nitro-5,8-dichloroisoquinoline (12). A suspension of 7-nitro-
5,8-dichloroisoquinoline 12 (13.0 kg, 53.5 mol) and the 5%
w/w platinum on charcoal (50% wet paste) (2.6 kg) in acetic
acid (19.5 L) and methanol (130 L) was hydrogenated at 20
°C and 3.5 barg for 30 min. The reaction mixture was the heated
to 50 °C and then stirred for 8 h. The suspension was then
treated with water (65 L), the temperature was then increased
to ∼75 °C, and the mixture stirred for 10 min. The suspension
was then filtered while still hot and the catalyst bed washed
with methanol (13 L). The combined filtrate and wash were
then allowed to cool to 20 °C, aged for 3 h, then cooled to 5
°C and aged for 16 h. The solid was then filtered, washed with
methanol (13 L), and blown dry. The damp cake was then
suspended in THF (130 L), heated to 50 °C, and treated with
2 M aqueous sodium hydroxide solution (26 L). The mixture
was then stirred at 50 °C for 1 h to give a clear biphasic solution.
The layers were then allowed to separate, and the lower aqueous
layer was removed. The THF solution was then concentrated
to 65 L and cooled to 0 °C over 2 h. During the cooling, after
∼1 h from the start of the cooling ramp, water (91 L) was added
over 1 h. After stirring the resultant slurry at 0 °C for 16 h, the
solid was filtered off, washed with water (2 × 13 L), and dried
to give a cream-colored solid (6.3 kg, 55% yield): mp 198-200
°C. 1H NMR (400 MHz, d6-DMSO) δ 6.78 (s, 1H), 5.35 (br s,
NH2, 2H), 3.72 (s, 2H), 2.87 (t, J ) 6.0 Hz, 2H), 2.47 (t, J )
7-Nitro-5,8-dichloroisoquinoline (12) from 5,8-Dichlor-
oisoquinoline (11). Nitronium tetrafluoroborate (900 g, 5.35
mol) followed by 5,8-dichloroisoquinoline 11 (500 g, 2.52 mol)
(21) Although the use of nitronium tetrafluoroborate was successfully
demonstrated during the scale-up campaign, concerns about the long-
term availability in commercial quantities of the reagent caused us to
evaluate a further route to SB-406725A 1. Reduction of 5,8-
dichloroisoquinoline 11 to 5,8-dichlorotetrahydroisoquinoline followed
by nitration using potassium nitrate and 98% sulphuric acid gave a
∼3:1 mixture of 7-nitro and 6-nitro isomers, respectively. We were
able to separate these isomers by recrystallisation from methanol in
50% yield overall from 5,8-dichlorotetrahydroisoquinoline. Reduction
of the nitro group of 7-nitro-5,8-dichlorotetrahydroisoquinoline could
then be achieved under dissolving metal conditions to give the amino
tetrahydroisoquinoline 13, and this could then be converted into SB-
406725 1 via the NaHMDS coupling methodology as described above.
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5.9 Hz, 2H). 13C NMR (100 MHz, d6-DMSO) δ 143.2 (C),
136.2 (C), 132.0 (C), 121.3 (C), 114.1 (C), 112.4 (CH), 46.7
(CH2), 42.5 (CH2), 26.1 (CH2). MS (ES +VE): m/z 217, 258
(M+ + H, M+ + MeCN).
pressure. The reaction mixture was then diluted with propan-
1-ol (105 L) and distilled at reduced pressure back to ∼10 vol
(105 L). The reaction mixture was then diluted with propan-
1-ol (105 L) and distilled at reduced pressure back to ∼10 vol
(105 L). The reaction mixture was then diluted with propan-
1-ol (105 L) and distilled at reduced pressure back to ∼10 vol
(105 L). The reaction mixture was then heated to 88 °C to give
a yellow solution. Water (10.5 kg) and 36% w/w HCl (3.0 kg)
were then added, and the reaction was kept at 88 °C. The
reaction was then seeded with SB-406725A (0.01 kg). The
reaction mixture was aged at 88 °C for 30 min, cooled to 0 °C
over 2 h, and then aged at 0 °C for 30 min. The resultant white
slurry was then filtered and washed with propan-1-ol at 0 °C
(32 L). The cake was then pulled dry and oven-dried to give a
white crystalline solid (10.2 kg, 88% yield): mp 241-244 °C
(decomp). 1H NMR (400 MHz, d6-DMSO) δ 10.30 (br s, 1H),
9.86 (br s, 2H), 8.24 (d, J ) 2.5 Hz, 1H), 8.16 (dd, J ) 2.5 Hz,
8.8 Hz, 1H), 7.72 (s, 1H), 7.35 (d, J ) 9.3 Hz, 1H), 4.93 (sep,
J ) 6.0 Hz, 1H), 4.29 (s, 2H), 3.42 (t, J ) 6.2 Hz, 2H), 3.02
(t, J ) 6.1 Hz, 2H), 2.59 (s, 3H), 1.39 (d, J ) 6.1 Hz, 6H). 13C
NMR (100 MHz, d6-DMSO) δ 198.7 (C), 164.4 (C), 159.4 (C),
134.8 (C), 133.2 (CH), 131.2 (C), 129.9 (C), 129.8 (C), 129.8
(CH), 128.3 (C), 127.2 (CH), 126.9 (C), 125.1 (C), 114.0 (CH),
71.0 (CH), 42.4 (CH2), 39.4 (CH2), 31.7 (CH3), 23.4 (CH2),
21.6 (CH3). MS (ES +VE): m/z 421 (M+ + H).
3-Acetyl-N-(5,8-dichloro-1,2,3,4-tetrahydro-7-isoquinoli-
nyl)-4-(1-methylethoxy)-benzamide (16) from 7-Amino-5,8-
dichlorotetrahydroisoquinoline (13). To a stirred slurry of
7-amino-5,8-dichlorotetrahydroisoquinoline 13 (9.5 kg, 43.8
mol) in THF (147 L) was added 3-acetyl-4-(1-methylethoxy)-
methylbenzoate 15 (12.8 kg, 54.2 mol) and the mixture cooled
to 0 °C. NaHMDS, 40% w/w in THF (119 L, 108.8 kg, 237.3
mol), was then added over ∼30 min, keeping the reaction
temperature below 5 °C, and the reaction was then stirred for
30 min. The reaction mixture was then treated with water (95
L), and the phases were then heated to 60 °C and mixed for 15
min before being allowed to settle for 15 min. The aqueous
phase was discarded, and the organic phase was then washed
with 30% w/w aqueous sodium chloride solution (95 L) at 60
°C. The yellow solution was then distilled to 170 L in volume
at atmospheric pressure and then cooled back to 60 °C before
being seeded with SB-406725 (9.5 g). The reaction mixture
was aged at 60 °C for 30 min, cooled to 0 °C over 2 h, and
then aged at 0 °C for 5 h. The resultant off-white slurry was
then filtered, washed with THF at 0 °C (19 L vol), and blown
dry. The wet cake was then slurried in water (95 L vol) at 50
°C for 4 h, cooled to 5 °C over 1 h, and aged at 5 °C for 1 h.
The resultant off-white slurry was filtered and washed with
water (19 L) at 5 °C and dried to give a cream-colored solid
Acknowledgment
We thank our R&D Chemical Development colleagues
Matthew Gray, Steve Hermitage, Rebecca Newton, Peter
Shapland, Charles Wade, and Andrew Whitehead from Syn-
thetic Chemistry for contributions to the conception of this
synthetic route; Paul Evans, Peter Hartley, Julian Nash, and
Andrew Share from Process Technologies for realization of the
route on a production scale; Laura Clow, Chris Emmott, and
John Roberts from Analytical Sciences; Richard Cox from
Technical Sourcing; and Keith Allworth and Julie Thomas from
Particle and Process Sciences and Engineering for their experi-
mental assistance.
1
(15.9 kg, 83% yield): mp 170-171 °C. H NMR (400 MHz,
d6-DMSO) δ 10.06 (br s, 1H), 8.21 (d, J ) 2.4 Hz, 1H), 8.11
(dd, J ) 2.4 Hz, 8.8 Hz, 1H), 7.54 (s, 1H), 7.31 (d, J ) 9.3
Hz, 1H), 4.90 (sep, J ) 6.0 Hz, 1H), 3.82 (s, 2H), 2.94 (t, J )
5.9 Hz, 2H), 2.63 (t, J ) 5.8 Hz, 2H), 2.56 (s, 3H), 1.37 (d, J
) 6.1 Hz, 6H). 13C NMR (100 MHz, d6-DMSO) δ 198.7 (C),
164.4 (C), 159.3 (C), 137.1 (C), 133.5 (C), 133.1 (CH), 132.9
(C), 131.5 (C), 129.7 (CH), 128.3 (C), 126.5 (C), 125.4 (CH),
125.4 (C), 113.9 (CH), 71.0 (CH), 46.8 (CH2), 46.8 (CH2), 31.7
(CH3), 26.8 (CH2), 21.6 (CH3). MS (ES +VE): m/z 421 (M+
+ H).
Supporting Information Available
3-Acetyl-N-(5,8-dichloro-1,2,3,4-tetrahydro-7-isoquinoli-
nyl)-4-(1-methylethoxy)-benzamide hydrochloride (1) from
3-Acetyl-N-(5,8-dichloro-1,2,3,4-tetrahydro-7-isoquinolinyl)-
4-(1-methylethoxy)-benzamide (16). A stirred slurry of SB-
406725 16 (10.5 kg, 24.9 mol) in THF (263 L) was heated to
60 °C to give a yellow solution. The solution was then clarified
by filtration through a 5 µm polypropylene filter cartridge. The
solution was then concentrated to ∼5 vol (53 L) at atmospheric
Analytical general methods and NMR, HPLC, and LC/MS
data of the final product and all intermediates in the new route.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Received for review August 4, 2009.
OP9002054
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