Concise synthesis of JN403, a novel nicotinic acetylcholine receptor 7 selective agonist

Article abstract of DOI:10.1080/00397910802663378

A three-step method for the synthesis of (S)-(1-aza-bicyclo[2.2.2]oct-3-yl) carbamic acid (S)-1-(2-fluorophenyl)ethyl ester HCl salt (12) was developed, starting from alcohol 3 and resulting in an overall yield of 50%. A key feature of the present study i

Full text of DOI:10.1080/00397910802663378

Synthetic Communications1, 39: 2640–2646, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802663378
Concise Synthesis of JN403, a Novel Nicotinic
Acetylcholine Receptor a7 Selective Agonist
ˇ
Xinglong Jiang, Kapa Prasad, and Oljan Repic
Process Research and Development, Novartis Pharmaceuticals
Corporation, East Hanover, New Jersey, USA
Abstract: A three-step method for the synthesis of (S)-(1-aza-bicyclo[2.2.2]oct-
3-yl)carbamic acid (S)-1-(2-fluorophenyl)ethyl ester HCl salt (12) was developed,
starting from alcohol 3 and resulting in an overall yield of 50%. A key feature of
the present study is the need to use a strong base such as n-butyllithium for
neutralizing the HCl salt of 5 during the condensation of 4 with 5.
Keywords: n-Butyllithium, condensation, hydrochloride salt, neutralization
INTRODUCTION
Nicotinic acetylcholine receptor (nAChR) a7–related mechanisms have
been implicated in sensory gating and cognitive processing and may
contribute to the pathophysiology of schizophrenia. Furthermore, a7
nAChR may play a role in pain and epilepsy. JN403 (1) was identified[1]
as an orally active a7 nChR agonist and was selected for further evalua-
tion in humans as a treatment for schizophrenia.
Received August 26, 2008.
Address correspondence to Dr. Xinglong Jiang, Process Research and
Development, Novartis Pharmaceuticals Corporation, One Health Plaza, East
Hanover, NJ 07936, USA. E-mail: xinglong.jiang@novartis.com
2640

Concise Synthesis of JN403
2641
Scheme 1. The research synthesis of 1.
The research synthesis[2] of 1 (Scheme 1) involved four steps with
four chromatographic purifications, yielding the drug substance in an
8% overall yield. The succinate salt was difficult to produce in a 1:1
stoichiometric ratio and was mostly amorphous. In view of these issues,
we looked at alternative strategies and at optimizing the current
synthesis.
RESULTS AND DISCUSSION
At the outset, we tried two alternative approaches for preparing 1 as
shown in Scheme 2. Route A is very attractive because it is a one-pot
operation. Isocyanate 8 was made in situ by treating 5 with (t-Boc)2O=
dimethylaminopyridine (DMAP) in the presence of N-methylmorpholine
in acetonitrile. Addition of 3 resulted in the isolation of 1 in 34% yield
after chromatography. In the second approach, trichloroacetamide 9
was used as a key intermediate, and the product was isolated in 65%
yield. Although these approaches appeared interesting because route A
was shorter than the research synthesis, the isolation of the drug
substance appeared problematic. In route B, a reasonable overall yield

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X. Jiang, K. Prasad, and O. Repic
2642
Scheme 2. Alternative approaches for preparing 1.
was obtained, but a highly toxic and corrosive reagent, trichloroacetyl
chloride, was used. Because the parallel approach of optimizing the
research synthesis proved to be more fruitful and because of time
constraints, we did not pursue these alternative strategies further.
Optimizations of the Synthesis of 3
In the research synthesis, 3 was produced in 91% ee by asymmetric reduc-
tion of 2 using commercial (–)-DIPCl. Alcohol 3 that was produced
under these conditions was of low optical purity and contaminated with
pinene. By replacing (–)-B-chlorodiisopinocamheylborane [(–)-DIPCl]
with (R)-MeCBS and BH3-N,N-diethylaniline (DEAN), we were able
to obtain 3 in 95.5% yield with 98.1% ee.[3] At this stage, the decision
was made to outsource this material.
Formation of Imidazolyl Carbamate (4)
In the research procedure, compound 3 and carbonyldiimidazole were
combined and heated at 50ꢀC in tetrahydrofuran (THF)=Et2O, and com-
pound 4 was obtained in 40% yield after chromatography. Symmetrical
carbonate 10, formed by the reaction of 3 with the intermediate 4, was
the major by-product produced under these conditions. By changing
the addition order (i.e., a slow addition of a THF solution of 3 to a solu-
tion of carbonyldiimidazole in THF at 50ꢀC) and increasing the ratio of
carbonyldiimidazole to 1.5 equiv, carbamate 4 was produced in almost
quantitative yield with acceptable purity, thus avoiding further purifica-
tion (Scheme 3).

Concise Synthesis of JN403
2643
Coupling of Carbamate 4 with Amine 5
Based on the research procedure, condensation of 4 with 5 in the presence
of sodium carbonate in DMF at 80ꢀC for 4 h afforded 1 in 27% yield after
chromatography. Based on our preliminary experimentation, this low
yield was attributed to the formation of significant amounts of by-
products 10 and 11 under these experimental conditions. The immediate
area of concern in this step was the insolubility of 5 under these condi-
tions, and we needed to find a facile method for neutralization of the
hydrochloride salt. To regenerate free amine, 5 was dissolved in water
and neutralized with aqueous sodium hydroxide. Extraction with organic
solvents [EtOAc or tert-butyl methyl ether (TBME)] gave a low yield of
the free amine, because the free amine is highly soluble in water. A few
alternatives were screened with the objectives of in situ regeneration of
the free amine. The first attempt was to conduct the reaction in toluene
with 50% aqueous sodium hydroxide as a base at 20ꢀC. About 10% of
1 was formed. Increasing the reaction temperature resulted in minor
Scheme 3. The optimized synthesis of 1.

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X. Jiang, K. Prasad, and O. Repic
2644
change only. The poor yield of 1 was attributed to the hydrolysis of 4 and
1 under these basic aqueous conditions. However, when n-BuLi, a strong
base was used, 1 was formed in a good yield within 1 h at 55ꢀC, and these
conditions were selected for scaleup.
Preparation of HCl Salt 12
The succinate salt of 1 was originally chosen as the salt form. This salt
was prepared by dissolving 1 (46.9 mmol) and succinic acid (49 mmol)
in 1,4-dioxane and water at 50ꢀC. Cooling the solution in an ice bath
and addition of TBME resulted in the precipitation of the salt. Because
the precipitated salt was sticky, isolation became problematic. In addi-
tion, as the 1:1 ratio was not reproducible, we looked for other crystalline
salts forms and found that the hydrochloride salt of 1 could be formed by
treatment of crude 1 in ethyl acetate with hydrogen chloride. Not only
did this salt turn out to be crystalline and easy to filter, most impurities
from previous steps were also removed in the mother liquor. With this
salt-formation procedure, 12 was prepared in good yield and with good
purity.
CONCLUSIONS
In conclusion, an optimized method for the preparation of 1 in good yield
and of good quality has been presented. The highlights of the present
work are the formation of imidazolecarbamate in quantitative yield by
slow addition of 3 in THF to a solution of carbonyldiimidazole and
the need to use a strong base such as n-butyllithium for neutralization
of the di-HCl salt 5.
EXPERIMENTAL
Melting points were measured on a Mel-Temp 3.0 melting-point appara-
1
tus and are uncorrected. H and 13C NMR spectra were recorded on
Bruker Avance 400 or Bruker Avance 500 instruments. Chemical shifts
are given on a d (ppm) scale. Enantiomeric purity of compounds was
determined by chiral high-performance liquid chromatography (HPLC).
For compound 1, a Chiralpak AS-H 4.6-mm ꢁ 250-mm column was
used. The mobile phase was hexane=2-propanol=diethylamine 83:17:0.1.
The chiral method conditions were isocratic run for 30 min, column
temperature 20 ꢂ 5ꢀC, flow rate 0.7 mL=min, and wavelength 230 nm.

Concise Synthesis of JN403
2645
Imidazole-1-carboxylic Acid (S)-1-(2-Fluorophenyl)ethyl Ester (4)
1,10-Carbonyldiimidazole (86.8 g, 0.54 mol) and tetrahydrofuran
(500 mL, 444.5 g) were added to a 1-L, three-necked flask, and the
resulting suspension was stirred and heated to 52 ꢂ 3ꢀC. A solution of
3 (50 g, 0.36 mol in 20 mL of THF) was added slowly to the resulting
solution, and the mixture was stirred at this temperature for 1 h. The
mixture was quenched with tert-butyl methyl ether (500 mL, 374 g)
and water (100 mL, 100 g). The two layers were separated, and the ora-
ganic layer was washed with 5% sodium bicarbonate solution (100 mL).
The organic layer was separated, washed successively with water
(100 mL) and saturated sodium chloride solution (100 mL), dried with
magnesium sulfate (7.0 g), filtered, and evaporated to dryness under
reduced vacuum to give 4 as an oil (82.0 g, 98% yield). 1H NMR
(CDCl3) d 1.75 (d, J ¼ 6.6 Hz, 3H), 6.35 (q, J ¼ 6.6 Hz, 1H), 7.06–7.21
(m, 3H), 7.32–7.45 (m, 3H), 8.16 (s, 1H); 13C NMR (CDCl3) d 20.94,
71.74, 115.8, 116.1, 117.1, 124.3, 124.6, 126.8, 127.1, 127.3, 130.4,
135.1, 137.1, 147.8, 158.2, 161.5.
(S)-(1-Aza-bicyclo)2.2.2]oct-3-yl)carbamic Acid
(S)-1-(2-Fluorophenyl)ethyl Ester (1)
A 1-L, three-necked flask was charged with 5 (65.7 g, 0.33 mol) and
THF (450 mL). The suspension was stirred and cooled to 0 ꢂ 5ꢀC,
followed by the slow addition of n-butyllithium (257.4 mL, 2.5 M in
hexane, 0.64 mol) while maintaining the temperature at 0 ꢂ 5ꢀC. The
reaction mixture was allowed to warm to room temperature over 1 h
and cooled back to 0–5ꢀC. A solution of 4 (70.26 g, 0.30 mol dissolved
in 20 mL of THF) was slowly added. The reaction mixture was warmed
and heated at 55 ꢂ 3ꢀC for 2 h. The mixture was evaporated to dryness,
and tert-butyl methyl ether (650 mL) and water (200 mL) were added.
The two layers were separated, and the oraganic layer was washed twice
with water (200 mL). The organic layer was separated, washed with
brine, and evaporated to dryness under vacuum to give 1 (74.09 g,
1
84.5% yield); mp 84ꢀC; MS (M þ 1) m=z 293.2; H NMR (CDCl3) d
1.32–1.50 (m, 1H), 1.55 (d, J ¼ 6.6 Hz, 3H), 1.53–1.65 (m, 3H), 1.85
(s, 1H), 2.47 (dd, J ¼ 15 Hz, 6 Hz, 1H), 2.75–2.85 (m, 4H), 3.32 (t,
J ¼ 6 Hz, 1H), 3.68 (s, 1H), 5.06 (s, 1H), 6.04 (m, 1H), 7.01–7.02 (m,
1H), 7.06–7.12 (m, 1H), 7.18–7.20 (m, 1H), 7.21–7.23 (m, 1H); 13C
NMR (CDCl3) d 19.95, 21.49, 25.58, 25.84, 46.41, 47.41, 48.10, 56.21,
67.34, 115.46, 115.74, 124.17, 127.15, 129.15, 129.25, 129.47, 155.3,
158.1, 161.3.

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X. Jiang, K. Prasad, and O. Repic
2646
(S)-(1-Aza-bicyclo)[2.2.2]oct-3-yl)carbamic Acid
(S)-1-(2-Fluorophenyl)ethyl Ester HCl Salt (12)
A 1-L, three-necked flask was charged with 1 (74.1 g, 0.254 mol) and ethyl
acetate (300 mL). The resulting solution was stirred and cooled to
0 ꢂ 3ꢀC. Hydrogen chloride (81 mL in ethyl acetate, 0.1375 g=mL,
0.30 mol) was slowly added at a rate to maintain the temperature at
0 ꢂ 3ꢀC (30 min). After the addition, the pH of the suspension was
checked with pH paper; the pH should be less than 4. The reaction
mixture was stirred at this temperature for 1 h. The suspension was
filtered and washed twice with ethyl acetate (75 mL), and the solid was
dried at 65ꢀC for 14 h under vacuum to give 60.3 g of 12 (61% yield);
mp 203ꢀC; MS (M þ 1) m=z 293.2. Anal. calcd. for C16H22FClN2O2: C,
58.44; H, 6.74; Cl, 10.78; N, 8.52. Found: C, 58.24; H, 6.71; Cl, 10.80;
1
N, 8.61. H NMR (CDCl3) d 1.49 (d, J ¼ 6.6 Hz, 3H), 1.59–1.68 (m,
1H), 1.72–1.88 (m, 2H), 1.92–1.98 (m, 2H), 2.19–2.22 (m, 1H),
3.05–3.18 (m, 4H), 3.31 (brs, 1H), 3.50–3.55 (m, 1H), 3.86 (brs, 1H),
7.17–7.25 (m, 2H), 7.32–7.38 (m, 1H), 7.42–7.48 (m, 1H), 7.85 (d,
J ¼ 6.6 Hz, 1H), 10.5 (s, 1H); 13C NMR (CDCl3) d 16.70, 21.13, 21.20,
24.44, 44.60, 45.20, 51.01, 66.01, 115.23, 115.52, 124.54, 124.59, 126.94,
126.99, 129.03, 129.20, 129.49, 129.60, 154.86, 157.35, 160.60.
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3. Garrett, C. E.; Prasad, K.; Repic, O.; Blacklock, T. J. The enantioselective
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