Improved synthesis of RO4858542, a 5-HT6 receptor antagonist

Article abstract of DOI:10.1021/op900319p

An improved synthesis of a 5-HT6 antagonist is described. A problematic amide reduction step was avoided by a reductive amination. Overall, 2.9 kg was produced over 6 steps with an overall yield of 56%.

Full text of DOI:10.1021/op900319p

Organic Process Research & Development 2010, 14, 470–473
Improved Synthesis of RO4858542, a 5-HT6 Receptor Antagonist
Qingwu Jin,* Michael Welch, and Lawrence Fisher
GTS Chemical Synthesis, Roche Palo Alto, LLC, 3431 HillView AVenue, Palo Alto, California 94304, U.S.A.
Abstract:
aromatic displacement of fluorides;2 however, the conditions
were ineffective for this particular transformation.
An improved synthesis of a 5-HT6 antagonist is described. A
problematic amide reduction step was avoided by a reduc-
tive amination. Overall, 2.9 kg was produced over 6 steps
with an overall yield of 56%.
In order to produce the initial batch for toxicity studies, we
followed the route shown in the scheme 1 for the remainder of
the synthesis. We replaced borane-DMS with borane-THF
for the double reduction because borane-DMS has unpleasant
odor. For the urea formation, we replaced triphosgene with the
safer reagent 1,1′-carbonyldiimidazole (CDI). The cyclization
was carried out in acetonitrile, and the product crystallized from
the reaction mixture and allowed for removal of a significant
amount of the impurities generated in the double reduction step.
Removal of the t-BOC group and the HCl salt formation was
achieved using aqueous HCl/methanol. Overall, 400 g of 1 were
produced in 20% yield over 6 steps.
After delivering material for the initial toxicity studies, we
returned to further improving the scalability of the synthesis.
We decided to prepare benzylamine 8 as it lacks the amide
bond that could be cleaved during the reduction of the nitrile
group. Reductive amination of 6 was carried out using sodium
triacetoxyborohydride (Scheme 4).3 We found that the aromatic
displacement could be cleanly carried out using 5 equiv of
piperazine instead of N-Boc-piperazine if run in hot (80 °C)
DMSO. DIEA was needed when 5 equiv of piperazine was
used. After water quench, the product was extracted into ethyl
acetate and reacted with di-tert-butyl dicarbonate. Upon crystal-
lization from isopropanol, amine 10 was obtained in 93% yield
over two steps. The subsequent nitrile reduction was carried
out using NaBH4/BF3-Et2O. This reagent offered an advantage
over borane-THF by reducing the reaction volume. The amine
was not isolated but instead was directly converted to urea 5
by reaction with 1,1′-carbonyldiimidazole. Boc deprotection was
carried out as before to provide compound 1. Overall, 2.9 kg
of RO4858542 were produced in 56% yield over 6 steps.
Introduction
RO4858542 (1) is a 5-HT6 antagonist developed at Roche
Palo Alto for central nervous system (CNS) indications includ-
ing Parkinson’s disease.1 This compound was first synthesized
by our medicinal chemists using the route shown in Scheme 1.
Displacement of one of the nitro groups of 2,6-dinitrobenzoni-
trile provided a piperazine derivative 2. Reduction of the nitro
group and acylation provided amide 3. The nitrile group and
the amide group were simultaneously reduced. Cyclic urea
formation followed by deprotection of the t-Boc group and HCl
salt formation afforded compound 1. There were several issues
that needed to be addressed prior to further scale-up: The starting
material, 2,6-dinitrobenzonitrile, had limited commercial avail-
ability; the double reduction of compound 3 was low yielding
and produced significant amounts of impurities resulting from
the amide bond cleavage, and triphosgene utilized for the urea
formation is toxic and odorous. These issues have been
successfully addressed and are described below.
Results and Discussion
2-Chloro-6-nitrobenzonitrile was tested and abandoned as a
new substrate because displacement of the nitro group was
favored over the chloride (Scheme 2). Instead, we turned our
attention to 2-amino-6-fluorobenzonitrile (6). This compound
is readily available in bulk quantities. The amino group was
acylated to provide amide 7 (Scheme 3), which was isolated
by crystallization upon the addition of water.
Attention then turned toward the displacement of the fluoride
by BOC protected piperazine. Various conditions were tested
before the suitable reaction conditions were found. The results
from the screening studies are shown in Table 1. The use of
DIEA as a base in DMSO yielded the best results. The reaction
did not proceed when TEA was used as a base, probably due
to the lower temperature. The reaction using DBU generated a
complex mixture, with 20-30% of the mixture being the desired
product. KF/Al2O3 was successfully used in the past for the
Conclusions
In conclusion, we developed a new, efficient synthetic route
for a 5-HT6 receptor antagonist. Key improved steps in the
process are the reductive amination of 2-amino-6-fluoroben-
zonitrile and aromatic displacement of the fluorine using
piperazine. The use of 2-amino-6-fluorobenzonitrile instead of
2,6-dinitrobenzonitrile addressed the issue of starting material
availability. Introduction of benzyl group onto an amine via
the reductive amination avoided a low-yielding amide reduction.
* Author for correspondence. Telephone: 1-650-855-5838. Fax: 1-650-855-
1270. E-mail: qingwu.jin@roche.com.
(1) (a) Berger, J.; Flippin, L. A.; Greenhouse, R.; Jaime-Figueroa, S.;
Liu, Y.; Miller, A. K.; Putman, D. G.; Weimhardt, K. K.; Zhao,
S. H. U. S. Patent 1999/005958934, 1999. (b) Maag, H.; Sui, M.;
Zhao, S. H. U. S. Patent 2004/0092512, 2004. (c) Bonhaus, S. W.;
Martin, R. S. U. S. Patent 2006/0069094, 2006. (d) Sui, M.; Zhao,
S. H. WO/2005/067933, 2005.
(2) Sawyer, J. S.; Schmittling, E. A.; Palkowitz, J. A.; Smith, W. J., III. J.
Org. Chem. 1998, 63, 6338.
(3) Abdel-Magid, A. F.; Maryanoff, C. A.; Carson, K. G. Tetrahedron Lett.
1990, 31, 5595.
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Vol. 14, No. 2, 2010 / Organic Process Research & Development
10.1021/op900319p  2010 American Chemical Society
Published on Web 01/29/2010

Scheme 1. Original synthesis of RO4858542a
a
Reagents and conditions: a) N-Boc-piperazine, DMF, 50 °C. b) H2, Pd/C. c) 3-Fluorobenzoyl chloride, THF, triethylamine. d) BH3-Me2S, THF, reflux. e) triphosgene,
CH2Cl2, triethylamine. f) HCl, EtOH.
Experimental Section
Scheme 2. Reaction of 2-chloro-6-nitrobenzonitrile and
N-Boc-piperazine
The NMR spectra were obtained at 300 and 75 MHz, for
1H and 13C, respectively. Drying of products and rotary
evaporations were carried out under 25-28 inHg house vacuum.
N-(2-Cyano-3-fluorophenyl)-3-fluorobenzamide (7). A
solution of 2-amino-6-fluorobenzonitrile (167 g,1.23 mol) and
pyridine (7 L) was cooled to 0-5 °C and a solution of
3-fluorobenzoyl chloride (195 g, 1.23 mol) in THF (167 mL)
was added at e10 °C. The reaction mixture was stirred for 3 h
while allowing it warm to ambient temperature. Water (8 L)
was added over 1 h. The white slurry was filtered and washed
with water (2 × 1.5 L). Drying overnight at 50 °C in a vacuum
oven provided N-(2-cyano-3-fluorophenyl)-3-fluorobenzamide
(7) (289 g, 91%). 1H NMR [DMSO-d6] δ 7.39-7.48 (m, 2 H),
7.52 (m, 1.0 Hz, 1 H), 7.63 (m, 1 H), 7.76-7.89 (m, 3 H),
10.89 (s, 1 H). Anal. Calcd for C14H8F2N2O: C, 65.11; H, 3.12;
N, 10.85. Found: C, 65.01; H, 3.19; N, 10.91.
Scheme 3. Improved synthesis of amide 3a
a
Reagents and conditions: a) 3-Fluorobenzoyl chloride. b) N-Boc-piperazine,
DIEA, DMSO, 120 °C.
4-[2-Cyano-3-(3-fluorobenzoylamino)phenyl]piperazine-
1-carboxylic Acid tert-Butyl Ester (3). N-(2-Cyano-3-fluo-
rophenyl)-3-fluorobenzamide (7) (163 g, 0.63 mmol), N-Boc-
piperazine (163 g, 1.27 mmol), diisopropylethylamine (163 g,
1.26 mmol), and DMSO (650 mL) were heated at 120 °C for
60 h. The mixture was cooled to 30 °C and diluted with water
(400 mL). The mixture was extracted with EtOAc (5 × 200
mL) in a wash vessel. The organic layer was washed with water
(300 mL) and brine (300 mL). The organic layer was evapo-
rated. The residue was dissolved in isopropanol (500 mL) at
reflux. The solution was cooled to 45 °C, diluted with water
(450 mL), and seeded. After cooling to 18-22 °C, the mixture
was stirred for 15 h. The product was collected by filtration.
The cake was washed with water (2 × 200 mL) and hexanes
(2 × 150 mL). Drying in a vacuum oven at 55-60 °C provided
4-[2-cyano-3-(3-fluorobenzoylamino)phenyl]piperazine-1-car-
boxylic acid tert-butyl ester (3) as a white solid (210 g, 78%).
1H NMR [CDCl3] δ 1.49 (s, 9 H), 3.16 (m, 4 H), 3.65 (m, 4
H), 6.78 (dd, J ) 8.3, 0.8 Hz, 1 H), 7.30 (m, 1 H), 7.52 (m, 2
H), 7.67 (m, 2 H), 8.18 (dd, J ) 8.4, 0.7 Hz, 1 H), 8.36 (br s,
1 H). Anal. Calcd for C23H25FN4O3/0.2 M H2O: C, 64.53; H,
5.98; N, 13.09; Found: C, 64.55; H, 6.10; N, 13.02.
4-[1-(3-Fluorobenzyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-
5-yl]piperazine-1-carboxylic Acid tert-Butyl Ester (5). Syn-
thesis from 3. 4-[2-Cyano-3-(3-fluorobenzoylamino)phenyl]pip-
erazine-1-carboxylic acid tert-butyl ester (3) (863 g, 2.04 mol)
was chilled in an ice bath while borane-THF (1 M solution in
THF, 8 L) was added over 1 h while keeping the internal
temperature below 50 °C. The ice bath was removed, and the
reaction mixture was heated to reflux. After 4 h, the solution
was stirred overnight at room temperature. Methanol (420 mL)
was added while keeping the temperature below 40 °C. The
solution was evaporated, and the residue was dissolved in ethyl
acetate (4.7 L). The solution was washed with water (4 × 2.8
L). The organic layer was evaporated to afford diamine 4 as
an orange oil (804 g). The diamine (804 g) in acetonitrile (3.8
L) was added to 1,1′-carbonyldiimidazole (289 g, 1.78 mol).
The solution was stirred for 16 h at room temperature. The slurry
was filtered and washed with acetonitrile (4 × 400 mL). The
Vol. 14, No. 2, 2010 / Organic Process Research & Development
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471

Table 1. Reaction of fluoride 7 with N-Boc-piperazine
base
solvent
temp (°C)
time (h)
conversion (%)
notes
K2CO3
DMSO
DMSO
DMSO
DMF
140
120
120
120
120
110
120
120
24
24
20
20
20
20
45
45
11
0
KF-Al2O3/18-C-6
KOtBu
displacement of the fluoride by tert-butoxide
displacement of the fluoride by tert-butoxide
complex mixture
Cs2CO3
0
0
KOtBu
NMP
TEA
DBU
DIEA
DMSO
DMSO
DMSO
94
Scheme 4. Improved synthesis of RO4858542a
a Reagents and conditions: a) 3-Fluorobenzaldehyde, NaB(OAc)3H, AcOH. b) DMSO, piperazine. c) (Boc)2O. d) NaBH4, BF3-Et2O. e) 1,1′-Carbonyldiimidazole,
CH3CN, rt. f) HCl, EtOH.
solid was dried for 14 h at 60 °C under vacuum to provide
4-[1-(3-fluorobenzyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-5-yl]pip-
erazine-1-carboxylic acid tert-butyl ester (5). (527 g, 59% over
2 steps).
4-[2-Cyano-3-(3-fluorobenzoylamino)phenyl]piperazine-
1-carboxylic Acid tert-Butyl Ester (10). 2-Fluoro-6-(3-fluo-
robenzylamino)benzonitrile (3.65 kg, 14.1 mol), piperazine (5.01
kg, 58.2 mol), and DMSO (12.8 L) were heated at 80 °C for
5 h. The mixture was cooled to room temperature, and water
(18 L) was added. The mixture was extracted in the reactor
with EtOAc (20 L, then 10 L). The combined organic layers
were vacuum distilled to ∼19 L. The solution was transferred
to di-tert-butyl dicarbonate (3.59 kg, 16.1 mol). The mixture
was stirred overnight at room temperature. The solution was
vacuum distilled (25-28 inHg) at 20-50 °C to ∼15 L. The
vacuum distillation continued while adding 30 L of isopropanol
and keeping the volume at ∼15 L. The slurry was cooled for
3 h at 5-10 °C. The product was isolated by filtration and
washed with cold isopropanol (10 L). Drying in a vacuum oven
at 60 °C provided 4-[2-cyano-3-(3-fluorobenzylamino)phe-
nyl]piperazine-1-carboxylic acid tert-butyl ester (10) (5.62 kg,
91.6%). 1H NMR [DMSO-d6] δ 1.42 (s, 9 H), 3.00 (t, J ) 5.0
Hz, 4 H), 3.47 (t, J ) 4.4 Hz, 4 H), 4.42 (d, J ) 6.2 Hz, 2 H),
6.22 (d, J ) 8.4 Hz, 1 H), 6.28 (d, J ) 7.7 Hz, 1 H), 6.75 (m,
1 H), 7.04 (m, 1 H), 7.13-7.22 (m, 2 H), 7.36 (m, 1 H). Anal.
Calcd for C23H27FN4O2 H2O: C, 67.29; H, 6.63; N, 13.65;
Found: C, 67.41; H, 6.60; N, 13.80.
2-Fluoro-6-(3-fluorobenzylamino)benzonitrile (8). 2-Amino-
6-fluorobenzonitrile (2.27 kg, 1.00 equiv), acetic acid (21.4 kg),
trifluoroacetic acid (2.04 kg, 1.05 equiv), and 3-fluorobenzal-
dehyde (2.35 kg; 1.10 equiv) were heated at 35-40 °C for 1.5 h.
The mixture was slowly added to a slurry of sodium triac-
etoxyborohydride (95%, 5.95 kg, 1.60 equiv) in 2.4 kg acetic
acid while keeping the internal temperature <36 °C. After ∼30
min, additional sodium triacetoxyborohydride (0.96 kg) in acetic
acid (5.3 kg) was added. After an additional 30 min, water (36.5
kg) was added while keeping the internal temperature below
40 °C. The slurry was cooled to 6 °C, filtered, and washed with
water (3 × 11.4 kg). The filter cake was vacuum dried at 60
°C, providing 2-fluoro-6-(3-fluorobenzylamino)benzonitrile (8)
(3.675 kg, 90.3%). 1H NMR [DMSO-d6] δ 4.46 (d, J ) 6 0.2
Hz, 2 H), 6.44 (d, J ) 8.6 Hz, 1 H), 6.53 (m, 1 H), 7.06 (m, 1
H), 7.20 (m, 1 H), 7.26-7.41 (m, 3 H). Anal. Calcd for
C14H10F2N2: C, 68.85; H, 4.13; N, 11.47; Found: C, 68.68; H,
4.00; N, 11.54.
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4-[1-(3-Fluorobenzyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-
5-yl]piperazine-1-carboxylic Acid tert-Butyl Ester (5). Syn-
thesis from 10. 4-[2-Cyano-3-(3-fluorobenzylamino)phenyl]pip-
erazine-1-carboxylic acid tert-butyl ester (10) (6.20 kg, 14.6
mol), sodium borohydride (705 g, 18.7 mol), and THF (35 kg)
were cooled to -5 °C. BF3-etherate (3.5 kg, 24.6 mol) and THF
(2 kg) were added while keeping the reactor temperature below
10 °C. The solution was heated at 40-45 °C for 19 h and cooled
to 15-20 °C. Methanol (8.0 kg) was added over 1 h. The
mixture was stirred for 1 h at 15-20 °C and concentrated to
17 L under vacuum. The concentration continued while aceto-
nitrile (3 × 21 kg) was added, keeping the volume constant.
Acetonitrile (23 kg) was added, and the mixture was cooled to
15-20 °C. The solution was added to 1,1′-carbonyldiimidazole
(1.98 kg, 12.2 mmol) and acetonitrile (36.8 kg). The mixture
was stirred for 20 h at 15-20 °C. The product was isolated by
filtration and washed with acetonitrile (2 × 18 L). Drying for
15 h at 50 °C under vacuum afforded 4-[1-(3-fluorobenzyl)-
2-oxo-1,2,3,4-tetrahydroquinazolin-5-yl]piperazine-1-carboxy-
lic acid tert-butyl ester (5). (5.01 kg, 94%). 1H NMR [CDCl3]
δ 1.49 (s, 9 H), 2.79 (t, J ) 5.0 Hz, 4 H), 3.55 (br s, 4 H), 4.54
(d, J ) 1.7 Hz, 2 H), 5.10 (s, 2 H), 5.19 (s, 1 H), 6.48 (d, J )
7.7 Hz, 1 H), 6.74 (d, J ) 7.4 Hz, 1 H), 6.93 (m, 2 H), 7.08
(m, 2 H), 7.28 (m, 1 H). Anal. Calcd for C24H29FN4O3: C, 65.44;
H, 6.64; N, 12.72. Found: C, 65.42; H, 6.57; N, 12.83.
with methanol (2 × 8 kg). Drying at 60 °C under vacuum
afforded 1-(3-fluorobenzyl)-5-piperazin-1-yl-3,4-dihydro-1H-
quinazolin-2-one hydrochloric acid salt (1) (3.03 kg). The solid
was dissolved in isopropanol (55 kg) and water (28 kg) at 70
°C. The solution was filtered through a 5 µm filter and washed
with isopropanol (11 kg). The filtrate was concentrated under
vacuum to 45 L. Concentration continued while adding iso-
propanol (3-77 kg) and keeping the volume constant. At the
end of the distillation, the mixture was cooled to 15-20 °C
and stirred for 16 h. The slurry was filtered and washed with
isopropanol (2-11 kg). 1-(3-Fluorobenzyl)-5-piperazin-1-yl-
3,4-dihydro-1H-quinazolin-2-one hydrochloric acid salt (1) was
1
obtained as a white solid (2.89 kg, 71%). H NMR [DMSO-
d6] δ 3.00 (m, 4 H), 3.19 (m, 4 H), 4.35 (d, J ) 1.2 Hz, 2 H),
5.05 (s, 2 H), 6.53 (d, J ) 8.1 Hz, 1 H), 6.72 (d, J ) 7.9 Hz,
1 H), 7.01-7.16 (m, 4 H), 7.30-7.42 (m, 2 H), 9.39 (s, 2 H).
Anal. Calcd for C19H2FN4OCl (adjusted for 0.35 equiv of H2O):
C, 59.56; H, 5.97; N, 14.62; Cl, 9.41. Found: C, 59.56; H, 5.65;
N, 14.62; Cl, 9.26.
Acknowledgment
We are grateful to Yvonne Walbroehl, Timothy Lane, and
Meena Shrihari for providing analytical support for this project.
The Palo Alto Pilot Plant staff of Gary Hedden, Gary Byrge,
Jesus Dela Paz, Francis Onyegegbu, Gaudelio Salom, and Viel
Teixeira is thanked for their support during the pilot plant
scale-up.
1-(3-Fluorobenzyl)-5-piperazin-1-yl-3,4-dihydro-1H-
quinazolin-2-one Hydrochloric Acid Salt (1). 4-[1-(3-Fluo-
robenzyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-5-yl]piperazine-
1-carboxylic acid tert-butyl ester (5) (4.75 kg, 10.8 mol),
methanol (40 kg), and concd HCl (3.1 kg) were refluxed for
3 h and cooled to 15-20 °C. The slurry was filtered and washed
Received for review December 9, 2009.
OP900319P
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