An improved synthesis of Lu AA20465

Article abstract of DOI:10.1016/j.tetlet.2006.05.117

A solution phase synthesis for the preparation of the glycine transporter 1 (GlyT1) inhibitor Lu AA20465 is presented, which relies on the straightforward assembly of the target molecule through a series of innovative reaction steps. The key steps include a regioselective amination reaction, a chemoselective reduction of an aryl nitro group, a diazotization and iodination sequence under nonaqueous conditions and a copper catalyzed thioarylation reaction.

Full text of DOI:10.1016/j.tetlet.2006.05.117

Tetrahedron Letters 47 (2006) 5355–5357
An improved synthesis of Lu AA20465
Eva A. Krafft, Emmanuel Pinard and Andrew W. Thomas*
F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, Discovery Chemistry, CH-4070 Basel, Switzerland
Received 20 April 2006; revised 15 May 2006; accepted 17 May 2006
Available online 9 June 2006
Abstract—A solution phase synthesis for the preparation of the glycine transporter 1 (GlyT1) inhibitor Lu AA20465 is presented,
which relies on the straightforward assembly of the target molecule through a series of innovative reaction steps. The key steps
include a regioselective amination reaction, a chemoselective reduction of an aryl nitro group, a diazotization and iodination
sequence under nonaqueous conditions and a copper catalyzed thioarylation reaction.
ꢀ 2006 Elsevier Ltd. All rights reserved.
OH
Compelling evidence exists suggesting that an impair-
ment in NMDA neurotransmission is involved in the
pathophysiology of schizophrenia.1 As glycine is an
obligatory co-agonist at the NMDA receptor complex,2
one strategy, to restore the NMDA function in Schizo-
phrenic patients, is to inhibit GlyT1: a transporter
known to be co-expressed in the brain with NMDA
receptor and which is responsible for the selective reup-
take of glycine into glial and neuronal cells.3 As a result,
considerable efforts4 have been focused on the develop-
ment of a wide variety of selective GlyT1 inhibitors from
which Lu AA20465 1 was recently claimed by Lundbeck
to be in late stage preclinical development.5
H
N
O
HCl
S
Br
N
N
I
N
H2N
Cl
Cl
3
(rac-2)
MeO
Cl
1 Lu AA20465
Scheme 1. Lundbeck strategies for the synthesis of Lu AA20465.
1 (Scheme 2). Our strategy inherited the excellent regio-
selectivity already known for the reaction of 2-methyl-
piperazine with 4a in the racemic synthesis of 5.
Unsurprisingly, when using (R)-2-methylpiperazine,
the first step proceeded in excellent yield to afford 5 with
complete regioselective control. It is also important to
note that the use of the dinitro derivative 4b as the elec-
trophile (K2CO3, EtOH, H2O, reflux, 1 h) led to lower
yields (71%) of the desired product 5 with significant
amounts of the undesired 4-substituted product being
formed. We believed the low efficiency in the original
sequence of diazotization and thioarylation was due to
the presence of the piperazine NH. As a result, we
decided to protect this group, whereupon we quickly dis-
covered that a benzyloxycarbonyl (Cbz) group was the
favoured choice and 5 was efficiently transformed into
6, under standard conditions, in quantitative yield.
Selective reduction of the nitro group in the presence
of the Cl atom and the Cbz group was best performed
using an iron, acetic acid mixture to give 7 in 77% yield.
The only side product obtained was the acetyl protected
The synthesis of a range of close derivatives was origi-
nally developed on solid phase and involved a number
of relatively cumbersome steps, including the use of an
iron-assisted SNAr displacement reaction and a photo-
lytic decomplexation as key steps.6 Consequently the
team, at Lundbeck, developed two additional routes to
access molecules of this type (Scheme 1). The first
involved a solution phase approach which relied on a
low yielding copper-assisted diazotization (11%) and a
S-arylation reaction from rac-2 as a key step.7 A second
improved route involved the implementation of two
regioselective Pd-catalyzed reactions: a S-arylation and
a N-arylation reaction using the trihalo-benzene deriva-
tive 3 as a key building block.5
Herein we wish to report on our recent efforts to develop
a more practical, straightforward and scaleable route to
*
Corresponding author. Tel.: +41 61 688 50 48; fax: +41 61 688 87
14; e-mail: andrew.thomas@roche.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.117

5356
E. A. Krafft et al. / Tetrahedron Letters 47 (2006) 5355–5357
Cbz
N
Cbz
N
Cbz
N
Cbz
N
H
N
X
a)
b)
c)
d)
e)
O2N
N
N
N
N
N
O2N
O2N
H2N
Y
S
Cl
Cl
MeO
Cl
Cl
Cl
Cl
8 Y = I
9 Y = H
10
7
5
6
4a X = F
4b X = NO2
OBu-t
O
OH
H
N
O
N
N
N
N
f)
g)
h)
N
HCl
S
S
S
MeO
Cl
MeO
MeO
Cl
Cl
11
12
1 Lu AA20465
Scheme 2. Synthesis of Lu AA20465.11 Reagents and conditions: (a) (R)-2-methylpiperazine, Et3N, DMF, 80 ꢁC, 3 h, 98%; (b) CbzCl, CHCl3,
NaHCO3, 0 ꢁC, 98–100%; (c) Fe, AcOH, 60 ꢁC, overnight, 77%; (d) iAmNO2, CsI, CuI, I2, DME, 60 ꢁC, 1.5 h, 69%; (e) 4-methoxythiophenol, CuI
(5 mol %), N-methylglycine, KOH, dioxane, reflux, on, 63%; (f) HCl in dioxane (4 N), then concd HCl (dropwise), reflux, 3 · 1.5 h, 88%; (g) t-butyl
bromoacetate, Hunig’s base, DMF, rt, on, 91%; (h) HCl (5 N), dioxane, 60 ꢁC, 1 h, 69%.
¨
aniline in approximately 5% yield which could be easily
removed by chromatography. In our hands, the diazoti-
zation and S-arylation sequence, delivered the desired
compound 11 in yields of less than 10%, using (R)-2
according to the originally published route. When the
same reaction conditions were ran on the Cbz protected
compound 7, we routinely obtained yields of ꢀ30% for
the reduced product 9 with yields of less than 5% for
the desired product 10. As a result, we attempted to
proceed stepwise and, in the absence of the 4-methoxythio-
phenol, it was possible to isolate yields of up to 36% for
8. Since this was not suitable for further scale up, we
investigated alternative diazotization methods.8 The use
of a neutral nonaqueous method provided the desired
product 8 in a much improved 69% yield. After screening
a range of conditions,9 the subsequent S-arylation was
best performed following the methods developed by Liu
and co-workers,10 (employing N-methyl glycine as an
important additive) to afford 10 in 63% yield on a multi-
gram scale with minimum formation of the reduced
product 9. Cbz-deprotection was best achieved under
the acidic conditions detailed in Scheme 2 to provide 11
in 88% yield. It should be noted that standard hydrogen-
olytic methods failed. Appendage of the acetic acid unit
using ethyl bromoacetate, although proceeding in accept-
able yield (>50%) was deemed inefficient since basic
hydrolysis with NaOH caused significant difficulties in
the isolation of the final product. We found this sequence
was best performed by telescoping the remaining steps
AA20465 starting from (R)-methylpiperazine and 4-
chloro-2-fluoronitrobenzene 4. A main improvement
from the original route was the straightforward imple-
mentation of a Cbz protecting group strategy which,
although adds two more individual steps to the reaction
sequence, allowed all key steps to be performed in good
to excellent yields and facilitated the isolation of prepar-
atively useful quantities of the target compound. The
key steps include a regioselective amination reaction, a
chemoselective reduction of an aryl nitro group, a diazo-
tization and iodination sequence under nonaqueous
conditions and
reaction.
a copper catalyzed thioarylation
Acknowledgements
We would like to thank Axel Maier and Anke Kurt for
additional technical assistance.
References and notes
1. For a recent review see: Millan, M. J. Psychopharmacology
2005, 179, 30–53.
2. Danysz, W.; Parsons, C. G. Pharmacol. Rev. 1998, 50,
597–664.
3. (a) Eulenburg, V.; Armsen, W.; Betz, H.; Gomeza, J.
Trends in Biochemical Sciences 2005, 30, 325–333; (b)
Gomeza, J.; Ohno, K.; Betz, H. Curr. Opin. Drug
Discovery Develop. 2003, 6, 675–682.
where treatment of Hunig’s base with t-butyl bromoacet-
¨
4. For recent reviews see: (a) Sur, C.; Kinney, G. G. Expert
Opin. Investig. Drugs 2004, 13, 515–521; (b) Slassi, A.;
Egle, I. Expert Opin. Ther. Patents 2004, 14, 201–214.
5. Smith, G. Lecture presented at the International Sympo-
sium on Advances in Synthetic, Combinatorial and
Medicinal Chemistry (ASCMC), Moscow, Russia, 5–8
May 2004.
6. (a) Ruhland, T.; Bang, K. S.; Andersen, K. J. Org. Chem.
2002, 67, 5257–5268; (b) Smith, G.; Mikkelsen, G.;
Andersen, K.; Greve, D.; Ruhland, T.; Wren, S. P. WO
03053942.
ate in DMF, provided 12 in 91% yield followed by
hydrolysis in HCl (5 N) in dioxane to give the target com-
pound 1 Lu AA20465 in 69% yield. The use of t-butyl
bromoacetate was much preferred over the originally re-
ported ethyl bromoacetate since it offered significant
advantages in the late stage purification of the final
product.
In conclusion, we have developed an efficient 8-step
strategy for the enantioselective synthesis of 1 Lu

E. A. Krafft et al. / Tetrahedron Letters 47 (2006) 5355–5357
5357
7. Smith, G.; Ruhland, T.; Mikkelsen, G.; Andersen, K.;
Christoffersen, C. T.; Alifrangis, L. H.; Mork, A.; Wren,
S. P.; Harris, N.; Wyman, B. M.; Brandt, G. Bioorg. Med.
Chem. Lett. 2004, 14, 4027–4030.
8. (a) Chen, Y.; Freskos, J. N.; Gasiecki, A. F.; Grapper-
haus, M. L.; Hansen, D. W.; Heintz, R. M.; Khanna, I.
K.; Kolodziej, S. A.; Mategani, S.; Massa, M. A.;
McDonald, J. J.; Mischke, D. A.; Nagay, M. A.; Perrone,
E.; Schnmidt, M. A.; Spangler, D. P.; Talley, J. J.; Trevidi,
M.; Wynn, T. A.; Becker, D. P.; Rico, J. G. WO 04000811;
(b) Smith, W. B.; Ho, O. C. J. Org. Chem. 1990, 55, 2543–
2545.
9. For recent reviews see: (a) Ley, S. V.; Thomas, A. W.
Angew. Chem., Int. Ed. 2003, 42, 5400–5449; (b) Kunz, K.;
Scholz, U.; Ganzer, D. Synlett 2003, 2428–2439.
10. Deng, W.; Zou, Y.; Wang, Y.-F.; Liu, L.; Guo, Q.-X.
Synlett 2004, 1254–1258.
11. All compounds shown in Scheme 2, were individually
isolated and fully characterized by 1H NMR and MS with
optical rotation measured and purity assessed by HPLC.
Known compounds were compared to the previously
reported data.5 Selected Experimental Details for Key
reaction steps. Step (a): To a solution of 4-chloro-2-
fluoro-nitrobenzene 4 (5.0 g, 28.5 mmol) in DMF (56 mL)
and triethylamine (7.9 mL, 57.0 mmol) was added (R)-2-
methylpiperazine (2.85 g, 28.5 mmol) and the resulting
mixture was heated at 80 ꢁC for 3 h. After cooling to rt,
the mixture was poured into water and extracted with
ethyl acetate. Drying the combined organic layers over
sodium sulfate, followed by filtration, evaporation and
purification on silica gel (eluting with DCM–MeOH)
afforded 5 (7.13 g, 98%) as a light red solid. Step (c): To a
mixture of 6 (9.28 g, 24.0 mmol) in acetic acid (270 mL)
was added iron powder (8.1 g, 145 mmol) and the resulting
mixture was heated at 60 ꢁC overnight. After cooling to rt,
the mixture was evaporated and slurried in ethyl acetate. It
was then filtered and the filtrate poured into water and
extracted with ethyl acetate. Drying the combined organic
layers over sodium sulfate, followed by filtration, evapo-
ration and purification on silica gel (eluting with EtOAc–
heptane) afforded 7 (6.56 g, 77%) as a light yellow gum.
Step (d): To a solution of 7 (5.4 g, 15 mmol) in 1,2-
dimethoxyethane (63 mL) was successively added cesium
iodide (3.93 g, 15.0 mmol), iodine (1.92 g, 8.0 mmol),
cuprous iodide (893 mg, 5.0 mmol) and isoamylnitrite
(9.53 mL, 91 mmol) and the resulting mixture was heated
at 60 ꢁC for 1.5 h. After cooling to rt, the mixture was
partitioned between ammonium chloride (saturated solu-
tion) and ethyl acetate and then the whole mixture filtered
through celite. The organic layer was then separated,
washed with sodium sulfite (5% solution), dried over
sodium sulfate, filtered, evaporated and purified on silica
gel (eluting with EtOAc–heptane) to afford 8 (4.93 g, 69%)
as a light yellow gum. Step (e): A solution of 8 (4.87 g,
10 mmol) in dioxane (21 mL) was added to a mixture of
copper iodide (99 mg, 1 mmol), 4-methoxythiophenol
(1.77 g, 12 mmol), N-methylglycine (184 mg, 2 mmol)
and potassium hydroxide pellets (1.69 g, 26 mmol). The
resulting light brown suspension was then heated under
reflux overnight. After cooling to rt, the mixture was
extracted with ethyl acetate. Drying the combined organic
layers over sodium sulfate, followed by filtration, evapo-
ration and purification on silica gel (eluting with EtOAc–
heptane) afforded 10 (3.13 g, 63%) as a colourless gum.