Synthesis of a [6-Pyridinyl-18F]-labelled fluoro derivative of WAY-100635 as a candidate radioligand for brain 5-HT1A receptor imaging with PET

Bioorganic & Medicinal Chemistry 11 (2003) 2769–2782

Synthesis of a [6-Pyridinyl-¹⁸F]-labelled Fluoro Derivative of

WAY-100635 as a Candidate Radioligand for Brain 5-HT_1A

Receptor Imaging with PET

Mylene Karramkam,^aFrancoise Hinnen,^aMyriam Berrehouma,^aChristophe Hlavacek,^a

Francoise Vaufrey,^aChrister Halldin,^bJulie A. McCarron,^cVictor W. Pike^cand

Frederic Dolle^a,*

a

´ ´ ´ ´ ´ ´

Service Hospitalier Frederic Joliot, Departement de Recherche Medicale, CEA, 4 place du General Leclerc,

F-91401 Orsay, France

^bKarolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital,

S-17176 Stockholm, Sweden

^cPET Radiopharmceutical Sciences Section, Molecular Imaging Branch, National Institute of Mental Health,

Building 10, Room B3C346A, 10 Center Drive, Bethesda, Maryland 20892-01003, USA

Received 17 January 2003; accepted 1 April 2003

Abstract—In recent years, considerable eﬀort has been spent on the design, synthesis and pharmacological characterization of

radioﬂuorinated derivatives of the 5-HT_1Areceptor antagonist, WAY-100635, for the in vivo study of these receptors in human

brain with PET. (Pyridinyl-6)-ﬂuoro- and (pyridinyl-5)-ﬂuoro-analogues of WAY-100635 (6-ﬂuoro and 5-ﬂuoro-WAY-100635, 5a/

6a) were synthesized as well as the corresponding chloro-, bromo- and nitro-derivatives as precursors for labelling (5b–d and 6b–d).

Comparative radiolabelling of these precursors with ﬂuorine-18 (positron-emitting isotope, 109.8 min half-life) clearly demonstrated

that only ortho-ﬂuorination in this pyridine series, and not meta-ﬂuorination, is of interest for the preparation of a radioligand by

nucleophilic heteroaromatic substitution. 6-[¹⁸F]Fluoro-WAY-100635 ([¹⁸F]5a) can be eﬃciently synthesized in one step, either

from the corresponding 6-bromo precursor (using conventional heating at 145 ^ꢀC for 10 min) or from the corresponding 6-nitro

precursor (using microwave activation at 100 W for 1 min). Typically, 15–25 mCi (0.55–0.92 GBq) of 6-[¹⁸F]ﬂuoro-WAY-100635

([¹⁸F]5a, 1–2 Ci/mmol or 37–72 GBq/mmol) were obtained in 50–70 min starting from a 100 mCi (3.7 GBq) aliquot of a batch of

cyclotron-produced [¹⁸F]ﬂuoride. This ¹⁸F-labelled radioligand is now being evaluated in PET studies.

Introduction

studying in vivo molecular interactions. It can play a

key-role both in elucidating the involvement of these

receptors in neuropsychiatric disorders,²in therapies

with already established pharmaceuticals^3,4or with

drugs under development.^5ꢁ7

The serotonergic system, with its diﬀerent receptor sub-

types, is one of the most important neurotransmitter

system in the brain and is involved in the regulation of

various physiological functions and states of mind. 5-

HT_1Areceptors in particular are strongly implicated in

neuropsychiatric disorders such as anxiety, depression

and schizophrenia.¹Positron Emission Tomography

(PET), a high-resolution, sensitive and non-invasive

imaging technique that can be used in humans, is the

most advanced technology currently available for

WAY-100635 (1, cyclohexanecarboxylic acid {2-[4-(2-

methoxy-phenyl)-piperazin-1-yl]-ethyl}-(pyridin-2-yl)-

amide, Fig. 1) labelled with carbon-11, a 20.4 min half-

life positron-emitter, has been established as the radi-

oligand of choice for the study of 5-HT_1Areceptors in

human brain in vivo using PET.^8ꢁ12However, this very

eﬀective antagonist radioligand ([¹¹C]WAY-100635,

[¹¹C]1) is rapidly metabolized and rapidly cleared from

plasma¹³which can reduce the ease of applying some

approaches to biomathematical analysis of the radioligand

*Corresponding author. Tel.: +33-1-69-86-77-04; fax: +33-1-69-86-

77-49; e-mail: frederic.dolle@cea.fr

doi:10.1016/S0968-0896(03)00225-6

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M. Karramkam et al. / Bioorg. Med. Chem. 11 (2003) 2769–2782

Figure 1. Chemical structures of WAY-100635 (1), FCWAY (2) and MPPF (3).

binding to 5-HT_1Areceptors. Moreover, the short half-

life of carbon-11 obliges the radioligand to be used local

to its production. The use of longer-lived positron-

emitting ﬂuorine-18 (t₁₌₂¼ 109:8 min) has the potential

to circumvent these issues.

substitution with ¹⁸F-labelled ﬂuoride ion appears today

as the method of choice for the highly eﬃcient synthesis

of radioligands of high speciﬁc activity for PET. How-

ever, compared to homoaromatic- and aliphatic

nucleophilic radioﬂuorinations,^27,28only few references

can be found in the literature describing nucleophilic

substitutions with [¹⁸F]ﬂuoride ion of heteroaromatic

compounds such as pyridines and only reactions invol-

ving ﬂuorination at the ortho-position have been inten-

sely studied. In particular, the scope of these

nucleophilic heteroaromatic ﬂuorinations with no-car-

rier-added [¹⁸F]ﬂuoride ion as its activated K[¹⁸F]F-

K₂₂₂complex was evaluated using the synthesis of 2-

[¹⁸F]ﬂuoropyridine as a model reaction.²⁹The potent

radioligands, nor-chloro[¹⁸F]ﬂuoroepibatidine ((Æ)-exo-

2-(6-[¹⁸F]ﬂuoro-3-pyridyl)-7-azabicyclo[2.2.1]heptane)^30ꢁ36

and 2-[¹⁸F]ﬂuoro-A-85380 (2-[¹⁸F]ﬂuoro-3-[2(S)-2-azeti-

dinylmethoxy]pyridine)^37ꢁ39were recently labelled with

ﬂuorine-18 at the ortho-position on the pyridine ring.

Heteroaromatic nucleophilic substitutions of the pyri-

dine ring at the meta-position has, to our knowledge

never been reported. The only example of a radio-

In recent years, considerable eﬀort has been spent on

the design, synthesis and pharmacological characteriza-

tion of ﬂuorinated derivatives of WAY-100635 for

radiolabelling with ﬂuorine-18. For example, FCWAY

(2, 4-ﬂuoro-cyclohexanecarboxylic acid {2-[4-(2-meth-

oxy-phenyl)-piperazin-1-yl]-ethyl}-pyridin-2-yl-amide,

Fig. 1) has been labelled with ﬂuorine-18 by nucleo-

philic aliphatic tosyl-to-ﬂuoro substitution.^14,15How-

ever, [¹⁸F]FCWAY ([¹⁸F]2) also show rapid metabolism

and in particular deﬂuorination, which eventually gives

rise to problematical [¹⁸F]ﬂuoride uptake in skull.¹⁶

Another ﬂuorinated derivative, MPPF (3, 4-ﬂuoro-N-

{2-[4-(2-methoxy-phenyl)-piperazin-1-yl]-ethyl}-N-pyridin-

2-yl-benzamide, Fig. 1) has been labelled with ﬂuorine-

18 by nucleophilic aromatic nitro-to-ﬂuoro sub-

stitution.^17ꢁ23[¹⁸F]MPPF ([¹⁸F]3) is currently under

validation for human PET studies and for quantifying

the endogenous ligand, serotonin, at the receptor

level.²⁴

synthesis of

a

meta-[¹⁸F]ﬂuoropyridine derivative

known to us is the preparation of N-(2-aminoethyl)-5-

[¹⁸F]ﬂuoropyridine-2-carboxamide, using a nitro-to-

ﬂuoro substitution on a chemical structure bearing a

strong electron-withdrawing group para to the leaving

group.⁴⁰

Halopyridinyl derivatives of WAY-100635 (4, Fig. 2)

have recently been described as potent 5-HT_1Aantago-

nists and only minor eﬀects on aﬃnity or intrinsic eﬃ-

cacy have been shown²⁵compared to the parent ligand.

These halopyridinyl derivatives were also labelled with

carbon-11, suggesting a promising interest in PET ima-

ging ([¹¹C]-4, Fig. 2).²⁶Fluoropyridinyl derivatives can

be labelled with ﬂuorine-18. Moreover, in compounds

presenting a pyridine ring, nucleophilic heteroaromatic

We herein report the synthesis of 6-ﬂuoro- and 5-ﬂuoro-

derivatives of WAY-100635 (Fig. 3), namely: N-(2-(1-

(4-(2-methoxyphenyl)piperazinyl)ethyl))-N-(2-(6-ﬂuoro)-

pyridinyl)cyclohexane carboxamide (5a, 6-ﬂuoro-WAY-

100635) and N-(2-(1-(4-(2-methoxyphenyl)piperazinyl)-

ethyl))-N-(2-(5-ﬂuoro)pyridinyl)cyclohexane carboxamide

Figure 2. Chemical structures of halopyridinyl derivatives of WAY-100635 (4, general formula), and in particular 6-[¹¹C]ﬂuoro-, 6-[¹¹C]bromo- and

5-[¹¹C]bromo-WAY-100635 ([¹¹C]-5a/5c/6c).

M. Karramkam et al. / Bioorg. Med. Chem. 11 (2003) 2769–2782

2771

Figure 3. Chemical structures of 6-[¹⁸F]ﬂuoro- and 5-[¹⁸F]ﬂuoro-WAY-100635 ([¹⁸F]-5a/6a).

(6a, 5-ﬂuoro-WAY-100635). We also report the synth-

esis of the 5- and 6-chloro-, 5- and 6-bromo- and the 5-

and 6-nitro- derivatives of WAY-100635 (5b–d and 6b–

d) as precursor for labelling. Finally, comparative radi-

olabelling by nucleophilic heteroaromatic substitution

with ﬂuorine-18 at the ortho- and meta-position from

the corresponding precursors (5b–d and 6b–d) using

both conventional heating and microwave activation

will be presented, leading to an eﬃcient preparation of

6-[¹⁸F]ﬂuoro-WAY-100635 ([¹⁸F]5a).

cleanly gave the corresponding piperazines 12a–c and

13a–c in 77–91% yields.

Reduction of the amide function with lithium alumi-

nium hydride (LAH, 3 equiv) in tetrahydrofuran (THF)

at room temperature gave the desired amines 14a–c and

15a–c in 51–73% yields (Scheme 2).

As for the corresponding 6- and 5-halo- derivatives,

reaction of 6- and 5-nitro-2-aminopyridine (7d and 8d)

with chloroacetyl chloride in THF gave the corre-

sponding N-pyridinyl-2-chloroacetamide 9d and 10d in

91 and 57% yields, respectively (Scheme 3). Reaction of

each 2-chloroacetamides (9d or 10d) with 1-(2-methox-

yphenyl)piperazine 11 in DMF cleanly gave the corre-

sponding piperazines, 12d and 13d, in 89 and 71% yield,

respectively. However, the corresponding amines, 14d

and 15d, could not be obtained by reduction of the

amides. The use of LAH in THF at room temperature

or lower temperature gave a complex mixture of com-

pounds, without showing the desired amines 14d and

15d. Reduction of an amide function in the presence of

an aromatic nitro function on the same chemical struc-

ture is well documented in the literature and recom-

mends the use of borane (diborane),^41ꢁ52borane-

dimethylsulﬁde complex^53ꢁ55or sodium borohydride-

boron triﬂuoride diethyletherate,^56,57usually in THF as

solvent. Using the conditions described above, we again

obtained complex mixtures and the desired amines, 14d

and 15d, could not be isolated. No example could be

Results and Discussion

Chemistry

The synthesis of all 6- and 5-halo- derivatives of WAY-

100635 (5a–c, 6a–c) started from the commercially

available corresponding 6- or 5-substituted 2-amino-

pyridines (7a–c, 8a–c).

Reaction of the 6- or 5-halo-2-aminopyridines (7a–c/8a–

c) with 1.5 equiv of chloroacetyl chloride in dichloro-

methane containing 1.5 equiv of triethylamine at room

temperature for 17 h gave the corresponding N-pyr-

idinyl-2-chloroacetamides 9a–c and 10a–c in 42–96%

yield (Scheme 1). Reaction of the 2-chloroacetamides

9a–c or 10a–c with 1 equiv of 1-(2-methoxyphenyl)-

piperazine 11 in N,N-dimethylformamide (DMF) con-

taining 2.5 equiv of potassium carbonate at 60 ^ꢀC for 5 h

Scheme 1. Preparation of 2-[1-(4-(2-methoxyphenyl)piperazinyl]-N-(2-pyridinyl)acetamides 12a–c and 13a–c.

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M. Karramkam et al. / Bioorg. Med. Chem. 11 (2003) 2769–2782

Scheme 2. Preparation of 1-(2-methoxyphenyl)-4-(2-(2-aminopyridinyl)-ethyl)piperazines 14a–c and 15a–c.

Scheme 3. Preparation of 2-[1-(4-(2-methoxyphenyl)piperazinyl]-N-(2-pyridinyl)acetamides 12d and 13d.

found in the literature where an amide function was

reduced in the presence of a nitro-pyridinyl function.

The 6- and 5-halo-derivatives were synthesized in four

chemical steps starting from the commercially available

corresponding 6- or 5-substituted 2-aminopyridines (7a–

c, 8a–c). 6-Fluoro-WAY-100635 (5a), 5-ﬂuoro-WAY-

100635 (6a) and the corresponding chloro- (5b and 6b)

and bromo-analogues (5c and 6c) were obtained in 36,

25, 29, 22, 57 and 39% overall yield, respectively. The 6-

and 5-nitro- derivatives were synthesized in three che-

mical steps, also using the corresponding 6- or 5-nitro-2-

aminopyridines (7d and 8d) and were obtained in 2 and

3% overall yields, respectively. During the preparation

of this manuscript, alternative chemical syntheses of 6-

ﬂuoro-WAY-100635 (5a), as well as of the 5- and 6-

bromo-analogues (5c and 6c) were published.²⁵5a And

5c were obtained starting from the appropriate com-

mercially available 2,6-dihalopyridine in two and four

chemical steps, respectively (3% yield for 5a and 26%

yield for 5c). 6c was synthesized from 2-amino-5-bro-

mopyridine in four chemical steps and 19% overall

yield.²⁵

In order to synthesize the amines 14d and 15d, 1-(2-

methoxyphenyl)piperazine 11 was reacted with 5 equiv

of 2-chloroethyl p-toluenesulfonate in acetonitrile con-

taining 1 equiv of triethylamine at room temperature for

40 h to give the 2-chloroethylpiperazine derivative 16 in

27% yield (Scheme 4). Reaction of 16 with 5- or 6-nitro-

2-aminopyridine (7d/8d) in reﬂuxing acetonitrile con-

taining 1.5 equiv of triethylamine for 24–48 h gave the

desired amines 14d and 15d in 10 and 17% yield,

respectively.

Reaction of the 6- and 5-substituted pyridinylamines

(14a–d/15a–d) with 1.5 equiv of cyclohexanecarbonyl

chloride in dichloromethane containing 1.5 equiv of

triethylamine at room temperature for 48 h gave the

corresponding amides (5a–d/6a–d) in 63–98% yields

(Scheme 5).

M. Karramkam et al. / Bioorg. Med. Chem. 11 (2003) 2769–2782

2773

Radiochemistry

(DMSO) with the activated K[¹⁸F]F-Kryptoﬁx¹222

complex⁵⁸as the no-carrier-added radioﬂuorinating

reactant (Kryptoﬁx¹222 (K₂₂₂): 4,7,13,16,21,24-hex-

aoxa-1,10-diazabicyclo[8.8.8]hexacosane) by either con-

ventional heating or microwave activation.

In a ﬁrst step, both halo- and nitro- derivatives at the 6-

and 5-position of the pyridine ring were evaluated for

their eﬀectiveness as precursors for the radiosynthesis of

6-[¹⁸F]ﬂuoro- and 5-[¹⁸F]ﬂuoro-WAY-100635 ([¹⁸F]5a/

6a) using nucleophilic heteroaromatic ﬂuorinations

(Scheme 6).

In a ﬁrst set of experiments, the inﬂuence of the leaving

group (Cl^ꢁ, Br^ꢁand NO^ꢁ₂) and the reaction time were

studied for both 6- and 5-substituted pyridine deriva-

tives, 5b–d and 6b–d, at 145 ^ꢀC. ADMSO solution

(600 mL) containing 4.0–6.0 mg of the appropriate

Introduction of the ﬂuorine-18 as no-carrier-added

[¹⁸F]ﬂuoride was attempted in dimethyl sulfoxide

Scheme 4. Preparation of 1-(2-methoxyphenyl)-4-(2-(2-aminopyridinyl)-ethyl)piperazines 14d and 15d.

Scheme 5. Preparation of N-(2-(1-(4-(2-methoxyphenyl)piperazinyl)ethyl))-N-(2-pyridinyl)cyclohexane carboxamide 5a–d and 6a–d.

Scheme 6. Preparation of 6-[¹⁸F]ﬂuoro- and 5-[¹⁸F]ﬂuoro-WAY-100635 ([¹⁸F]5a/6a).

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M. Karramkam et al. / Bioorg. Med. Chem. 11 (2003) 2769–2782

precursor for labelling (5b–d or 6b–d) was transferred to

30–60 mCi of the dried K[¹⁸F]F-K₂₂₂complex in a

reaction vial (Vacutainer¹tube). The tube (not sealed)

was then placed in a heating block at 145 ^ꢀC for 1–

30 min without stirring the contents.

In a ﬁnal set of experiments, in the absence of reactivity

towards nucleophilic hetero-aromatic substitution at the

meta-position, the inﬂuence of the leaving group (Cl^ꢁ,

Br^ꢁand NO^ꢁ₂) and the reaction time and conditions

were studied for the 5-substituted pyridine derivatives

6b–d only, by conventional heating at 150–250 ^ꢀC, for

1–30 min. The K[¹⁸F]F-K₂₂₂complex was ﬁrst dissolved

in 600 mL of DMSO and then added to a reaction vial

containing 4.0–6.0 mg of the appropriate precursor for

labelling (6b–d). Finally, the reaction vial was tightly

sealed and placed in a heating block at the desired tem-

perature (150, 200 and 250 ^ꢀC) for 1–30 min without

stirring the contents. Whatever the conditions used, the

5-substituted derivatives 6b–d were completely unreac-

tive and the desired 5-[¹⁸F]ﬂuoro-WAY-100635 ([¹⁸F]6a)

could not be detected.

As shown in Table 1, the 6-chloro-, 6-bromo- and 6-

nitro- derivatives (5b–d) were reactive under the condi-

tions described above (conventional heating, 145 ^ꢀC).

Using the 6-chloro and the 6-bromo- derivatives 5b and

5c, the yield of 6-[¹⁸F]ﬂuoro-WAY-100635 ([¹⁸F]5a)

increased with the reaction time up to 10 min (26 and

63% yield, respectively). High incorporation yields were

observed at 3 min for the 6-nitro- derivative (5d) (90%

yield). In each run, the remaining radioactivity at the

end of the experiment was measured and 85–95% of the

initial radioactivity placed in the vessel was still present.

The decrease in the radiochemical yield with time was

therefore not attributed to volatiles but to decomposi-

tion of the formed 6-[¹⁸F]ﬂuoropyridine derivative

([¹⁸F]5a). Whatever the conditions used, the 5-sub-

stituted derivatives 6b–d were completely unreactive.

Based on these results, optimized conditions where

selected for the preparation of 6-[¹⁸F]ﬂuoro-WAY-

100635 ([¹⁸F]5a). Introduction of the ﬂuorine-18 atom

was performed in DMSO with the activated K[¹⁸F]F-

K₂₂₂complex by either conventional heating at 145 ^ꢀC

for 10 min using the 6-bromopyridine derivative 5c as

precursor for labelling, or by microwave activation at

100 W for 1 min using the 6-nitropyridine derivative 5d.

After Sep-Pak separation, the reaction mixture obtained

from either 5c or 5d was puriﬁed by HPLC to give pure

6-[¹⁸F]ﬂuoro-WAY-100635 ([¹⁸F]5a). Typically, 15–

25 mCi (0.55–0.92 GBq) of 6-[¹⁸F]ﬂuoro-WAY-100635

([¹⁸F]5a, 1–2 Ci/mmol or 37–72 GBq/mmol) were easily

In another set of experiments, the inﬂuence of the leav-

ing group (Cl^ꢁ, Br^ꢁand NO^ꢁ₂) and the reaction time

were studied for both 5- and 6-substituted pyridine

derivatives, 5b–d and 6b–d, using microwave activation

at 100 W. ADMSO solution (600 mL) containing 4.0–

6.0 mg of the appropriate precursor for labelling (5b–d

or 6b–d) was transferred to 30–60 mCi of the dried

K[¹⁸F]F-K₂₂₂complex in a reaction vial (Vacutainer¹

tube). The tube (not sealed) was then placed in a dedi-

cated microwave oven and irradiated at 100 W for 1–

3 min without stirring the contents. As shown in Table

1, the 6-chloro- and the 6-bromo- derivative (5b and 5c)

but especially the 6-nitro- derivative (5d) were reactive

under the conditions described above (microwave irra-

diation, 100 W). Using the 6-chloro- and the 6-bromo-

derivatives (5b and 5c), the yield of 6-[¹⁸F]ﬂuoro-WAY-

100635 ([¹⁸F]5a) increased with the reaction time up to

3 min (19 and 61% yield, respectively). High incor-

poration yields were observed at 1 min for the 6-nitro-

derivative (5d) (93% yield). All 5-substituted derivatives

(5-chloro-, 5-bromo- and 5-nitro- derivatives 6b–d) were

again unreactive.

obtained in 50–70 min starting from

a 100 mCi

(3.7 GBq) aliquot of a cyclotron-produced [¹⁸F]ﬂuoride

production batch (15–25% non decay-corrected yield

based on the starting [¹⁸F]ﬂuoride). Formulation of

labelled product for iv injection was eﬀected as follows:

the HPLC solvents were removed by evaporation and

the residue was redissolved in physiological saline. The

solution was then ﬁltered through a sterile 0.22 mm Mil-

lipore ﬁlter. As demonstrated by HPLC analysis, the

radiopharmaceutical preparation was found to be

>95% chemically and >99% radiochemically pure and

was radiochemically stable for at least 120 min.

During the preparation of this manuscript, another

radiochemical preparation of 6-[¹⁸F]ﬂuoro-WAY-

100635 ([¹⁸F]5a) was presented (abstracts) at both the

48th Annual Meeting of the Society of Nuclear Medi-

cine (Toronto, Canada)⁵⁹and the XIVth International

Symposium on Radiopharmaceutical Chemistry (Inter-

laken, Switzerland).^60,61The authors used the same

approach using the 6-bromopyridine derivative 5c as

precursor for labelling but with diﬀerent experimental

conditions and reported low and variable radiochemical

yields.

Table 1. Yields of 6-[¹⁸F]ﬂuoro- and 5-[¹⁸F]ﬂuoro-WAY-100635

([¹⁸F]5a/6a) using conventional heating at 145 ^ꢀC or microwave acti-

vation at 100 W: inﬂuence of the reaction time and nature of the leav-

ing group

Heating 145 ^ꢀC

Microwaves 100 W

Reaction time (min) 1⁰3⁰6⁰10⁰20⁰30⁰

1⁰

2⁰

3⁰

5b

5c

5d

6b–d

- Cl

- Br

- NO₂

- X^a

1 14 18 26 28 27

5 43 55 63 54 51

79 90 83 80 70 70

6

12

52

—

0

19

61

—

0

21

93

0

Conclusion

The development of ¹⁸F-labelled PET radioligands for

imaging the 5-HT_1Areceptor with PET has been an

important goal in recent years. We have synthesized two

ﬂuorinated analogues of WAY-100635 (6-ﬂuoro and 5-

ﬂuoro-WAY-100635, 5a/6a) as well as the correspond-

ing chloro-, bromo- and nitro- derivatives (5b–d and 6b–d)

0

Conditions: 4.0–6.0 mg of precursor; K[¹⁸F]F-K₂₂₂complex: 30–

60 mCi (EOB, 1.11–2.22 GBq); Solvent: DMSO (600 mL); heating

block for 1–30 min at 145 ^ꢀC or microwave oven (100 W) for 1–3 min;

no stirring. Indicated yields are the average of three independent runs.

^aX:-Cl,-Br or NO₂.

M. Karramkam et al. / Bioorg. Med. Chem. 11 (2003) 2769–2782

2775

as precursors for labelling. Comparative radiolabelling

with ﬂuorine-18 from these precursors clearly demon-

strated that only ortho-ﬂuorination in this pyridine ser-

ies and not meta-ﬂuorination, is of interest for the

preparation of radiotracer by nucleophilic heteroaro-

matic substitution. 6-Fluoro-WAY-100635 (5a) can be

eﬃciently synthesized in one step either from the corre-

sponding 6-bromo precursor (using conventional heat-

ing at 145 ^ꢀC for 10 min) or from the corresponding 6-

nitro precursor (using microwave activation at 100 W

for 1 min). This ¹⁸F-labelled radioligand is now being

evaluated in PET studies.

for 1000 mL]; ﬂow rate: 2.0 mL/min; temperature: 30 ^ꢀC;

absorbance detection at l=220 nm.

Complementary data for the preparation and char-

acterisation of the synthesized compounds listed below

are also available in the literature. See recently pub-

lished reference²⁵for 5a, 5c and 6c.

Spectroscopies. NMR spectra were recorded on a Bruker

AMX (300 MHz) apparatus using the hydrogenated

residue of the deuteriated solvents (CDCl₃, d=7.24 ppm;

CD₂Cl₂, d=5.32 ppm; DMSO-d₆, d=2.50 ppm) and/

or TMS as internal standards for ¹H NMR as well

as the deuteriated solvents (CDCl₃, d=77.0 ppm;

CD₂Cl₂, d=53.8 ppm; DMSO-d₆, d=39.5 ppm; CD₃OD,

d=49.3 ppm) and/or TMS as internal standards for ¹³C

NMR. The chemical shifts are reported in ppm, down-

ﬁeld from TMS (s, d, t, dd, b for singlet, doublet, triplet,

doublet of doublet and broad, respectively). The mass

spectra (MS), DCI/NH₄⁺, were measured on a Nermag

R10-10 apparatus.

Experimental

General

Chemicals, TLCs and HPLCs. 2-Amino-6-halopyridines

(7a–c) and 2-amino-6-nitropyridine (7d) were purchased

from ERAS-Labo, France. 2-Amino-5-ﬂuoropyridine

(8a) was purchased from Apollo Scientiﬁc Ltd, UK. 2-

Amino-5-chloropyridine (8b), 2-amino-5-bromopyridine

(8c) and 2-amino-5-nitropyridine (8d) as well as all

other chemicals were purchased from Aldrich, Fluka or

Sigma France. All chemicals were used without further

puriﬁcation. TLCs were run on pre-coated plates of

silica gel 60F₂₅₄(Merck). The compounds were localized

(1) when possible at 254 nm using a UV-lamp and/or (2)

by iodine staining and/or (3) by dipping the TLC-plates

in a 1% ethanolic ninhydrin solution (or in a 1% aqu-

eous KMnO₄solution) and heating on a hot plate.

Radioactive spots were detected using a Berthold Tra-

ceMaster 20 automatic TLC linear analyser. Flash

chromatography was conducted on silica gel 63–200 mm

(Merck) at 0.3 bars (Ar). HPLCs (Equipment: Waters

or Shimadzu systems): [HPLC A]: Equipment: system

equipped with a Waters 600 Pump and Waters 600

Controller, a Shimadzu SPD10-AVP UV-multi-wave-

length detector; semipreparative C-18, Zorbax¹SB,

Hewlett Packard (250 ꢂ 9.4 mm); porosity: 5 mm; con-

ditions: isocratic elution with MeOH / aq 0.1 M ammo-

nium formate/TEA:75/25/0.3 (v/v/v); ﬂow rate: 6 mL/

min; temperature: RT; absorbance detection at

l=254 nm. [HPLC B]: Equipment: Waters system

equipped with a 510 pump, a 440 UV detector or a 481/

486 UV-multi-wavelength detector; semipreparative

SiO₂, Zorbax¹Rx-SIL, Hewlett Packard (250 ꢂ

21.3 mm); porosity: 7 mm; conditions: isocratic elution

with EtOAc/CHCl₃/TEA:30/70/0.1 (v/v/v); ﬂow rate:

7 mL/min; temperature: RT; absorbance detection at

l=254 nm. [HPLC C]: Equipment: Waters Alliance

2690 equipped with a UV spectrophotometer (Photo-

diode Array Detector, Waters 996) and a Berthold

LB509 radioactivity detector; column: analytical Sym-

metry-M¹C-18, Waters (3.9 ꢂ 150 mm); porosity: 5 mm;

conditions: isocratic elution with solvent A/solvent

B:35/65 (v:v) [solvent A:H₂O containing Low-UV PIC¹

B7 reagent (Waters), 20 mL for 1000 mL; solvent B:

H₂O/CH₃CN:50/50 (v:v) containing Low-UV PIC¹B7

reagent (% by weight: methanol (18–22%), heptane

sulfonic acid- sodium salts (4–6%), phosphate buﬀer

solution (3–7%), water (65–75%), pH 3, Waters), 20 mL

Radioisotope production. No-carrier-added aqueous

[¹⁸F]ﬂuoride ion was produced on a CGR-MeV 520

cyclotron by irradiation of a 2 mL water target using a

17 MeV proton beam on 95% enriched [¹⁸O]water by

the [¹⁸O(p,n)¹⁸F] nuclear reaction and was transferred

to the appropriate hot cell. Typical production: 550–

650 mCi (20.3–24.0 GBq) of [¹⁸F]F^-at the end of bom-

bardment for a 20 mA, 30 min (36,000 mC) irradiation. A

complete description of the target hardware and oper-

ation can be found in references.^35,39

Miscellaneous. Radiosyntheses using ﬂuorine-18, includ-

ing the HPLC puriﬁcations were performed in a 7.5 cm-

lead shielded cell using a computer assisted Zymate

robot system (Zymark corporation, USA). Microwave

activation was performed with a MicroWell 10 oven

(2.45 GHz), Labwell AB, Sweden. Speciﬁc radioactivity

was determined as follows: the area of the absorbance

peak corresponding to the radiolabelled product was

measured on the HPLC chromatogram and compared

to a standard curve relating mass to absorbance.

Chemistry

General procedure: 2-chloro-N-(2-(halo)pyridinyl)aceta-

mides (9a–c and 10a–c). To 20.0 mmol of the appro-

priate 2-amino-halopyridine (7a–c or 8a–c) dissolved in

200 mL of dichloromethane, were added dropwise at

room temperature, 4.20 mL of triethylamine (30.0 mmol,

1.5 equiv) and 2.39 mL of chloroacetyl chloride

(30.0 mmol, 1.5 equiv). The reaction mixture was stirred

at room temperature for 17 h. The reaction was then

stopped by addition of 10% aq NaHCO₃. The organic

layer was separated and the aqueous layer was extracted

twice with dichloromethane. The organic layers were

combined, washed once with water and brine, dried

over Na₂SO₄, ﬁltered and concentrated. The residue was

chromatographed on silica gel.

2-Chloro-N-(2-(6-ﬂuoro)pyridinyl)acetamide (9a). The

procedure described above was used with 2.0 g of 7a.

2776

M. Karramkam et al. / Bioorg. Med. Chem. 11 (2003) 2769–2782

Elution with CH₂Cl₂/EtOAc (90/10 to 50/50 v/v) gave

3.09 g of the desired product as a white solid (92%). R_f

(Heptane/EtOAc : 50/50 v/v) : 0.45. H NMR (CD₂Cl₂,

300.0K) : d: 8.75 (b, 1H); 8.06 (d, J: 6 Hz, 1H); 7.88 (dd,

J: 6 and 9 Hz, 1H); 6.75 (dd, J: 3 and 9 Hz, 1H); 4.23 (s,

2H). ¹³C NMR (CD₂Cl₂, 300.0K): d: 165.1 [C]; 162.4 [C,

d, J: 239 Hz]; 149.3 [C, d, J: 14 Hz]; 144.0 [CH, d, J:

8 Hz]; 110.8 [CH, d, J: 4 Hz]; 105.6 [CH, d, J: 35 Hz];

43.4 [CH₂].

General procedure: 2-chloro-N-(2-(nitro)pyridinyl)aceta-

mides (9d and 10d). To 5.0 mmol of the appropriate 2-

amino-nitropyridine (7d or 8d) dissolved in 40 mL of

THF, were added dropwise at room temperature, 1.05mL

of triethylamine (7.5 mmol, 1.5 equiv) and 0.600 mL of

chloroacetyl chloride (7.50 mmol, 1.5 equiv). The reac-

tion mixture was stirred at room temperature overnight.

The reaction was then stopped by addition of 10% aq

NaHCO₃. The organic layer was separated and the

aqueous layer was extracted twice with dichloromethane.

The organic layers were combined, washed once with

water and brine, dried over Na₂SO₄, ﬁltered and con-

centrated. The residue was chromatographed on silica gel.

1

2-Chloro-N-(2-(6-chloro)pyridinyl)acetamide (9b). The

procedure described above was used with 2.0 g of 7b.

Elution with CH₂Cl₂/EtOAc (90/10 to 50/50 v/v) gave

2.36 g of the desired product as a white solid (74%). R_f

1

(EtOAc/Heptane: 50/50 v/v): 0.50. H NMR (CD₂Cl₂,

2-Chloro-N-(2-(6-nitro)pyridinyl)acetamide (9d). The

procedure described above was used with 0.7 g of 7d.

Elution with CH₂Cl₂/heptane/THF (80/15/5 v/v/v) gave

0.99 g of the desired product as a yellow oil (91%). R_f

300.0K): d: 8.81 (b, 1H); 8.11 (d, J: 9.0 Hz, 1H); 7.71

(t, J: 9.0 Hz, 1H); 7.13 (d, J: 9.0 Hz, 1H); 4.22 (s, 2H).

¹³C NMR (CD₂Cl₂, 300.0K): d: 165.0 [C]; 150.7 [C];

148.5 [C]; 141.4 [CH]; 120.8 [CH]; 112.2 [CH]; 43.4

[CH₂].

1

(EtOAc/Heptane: 50/50 v/v): 0.50. H NMR (CD₂Cl₂,

300.0K): d: 11.48 (b, 1H); 8.47 (d, J: 9.0 Hz, 1H); 8.26 (t,

J: 9.0 Hz, 1H); 8.07 (d, J: 9.0 Hz, 1H); 4.41 (s, 2H). ¹³C

NMR (CD₂Cl₂, 300.0K): d: 166.2 [C]; 154.6 [C]; 150.5

[C]; 142.9 [CH]; 119.4 [CH]; 113.3 [CH]; 43.3 [CH₂].

2-Chloro-N-(2-(6-bromo)pyridinyl)acetamide (9c). The

procedure described above was used with 2.0 g of 7c.

Elution with CH₂Cl₂/EtOAc (90/10 to 50/50 v/v) gave

2.76 g of the desired product as a yellow oil (96%). R_f

2-Chloro-N-(2-(5-nitro)pyridinyl)acetamide (10d). The

procedure described above was used with 1.0 g of 8d.

Elution with CH₂Cl₂/heptane/THF (80/15/5 v/v/v) gave

0.89 g of the desired product as an orange solid (57%).

R_f(EtOAc/Heptane: 50/50 v/v): 0.55. ¹H NMR

(CD₂Cl₂, 300.0K): d: 11.52 (b, 1H); 9.20 (d, J: 2.0 Hz,

1H); 8.65 (dd, J: 2.0 and 9.0 Hz, 1H); 8.27 (d, J: 9.0 Hz,

1H); 4.44 (s, 2H). ¹³C NMR (CD₂Cl₂, 300.0K): d: 166.3

[C]; 155.5 [C]; 144.7 [CH]; 140.2 [C]; 134.4 [CH]; 112.7

[CH]; 43.4 [CH₂].

1

(EtOAc/Heptane: 50/50 v/v): 0.50. H NMR (CD₂Cl₂,

300.0K): d: 8.92 (b, 1H); 8.13 (d, J: 9.0 Hz, 1H); 7.59 (t,

J: 9.0 Hz, 1H); 7.27 (d, J: 9.0 Hz, 1H); 4.25 (s, 2H). ¹³C

NMR (CD₂Cl₂, 300.0K): d: 165.2 [C]; 151.0 [C]; 141.1

[CH]; 139.8 [C]; 124.7 [CH]; 112.7 [CH]; 43.4 [CH₂].

2-Chloro-N-(2-(5-ﬂuoro)pyridinyl)acetamide (10a). The

procedure described above was used with 1.0 g of 8a.

Elution with CH₂Cl₂/EtOAc (90/10 to 50/50 v/v) gave

1.34 g of the desired product as a white solid (80%). R_f

1

(Heptane/EtOAc: 50/50 v/v): 0.50. H NMR (CD₂Cl₂,

General procedure: 2-[1-(4-(2-methoxyphenyl)piperazinyl]-

N-(2-pyridinyl)acetamides (12a–d and 13a–d). To

14.63 mmol of the appropriate 2-chloro-N-(2-pyr-

idinyl)acetamide (9a–d or 10a–d) dissolved in 20 mL of

DMF was added a DMF solution (80 mL) containing 1-

(2-methoxyphenyl)piperazine (11, 2.81 g, 14.63 mmol,

1 equiv) and anhydrous K₂CO₃(5.05 g, 36.58 mmol,

2.5 equiv). The reaction mixture was stirred at 60 ^ꢀC for

5 h. The reaction was then stopped by addition of water

and the mixture was extracted with ethylacetate. The

organic layers were combined, washed with brine, dried

over Na₂SO₄, ﬁltered and concentrated. The residue was

chromatographed on silica gel.

300.0K): d: 8.91 (b, 1H); 8.24–8.14 (b, 2H); 7.49 (dt, J:

3.0 9.0 Hz, 1H); 4.21 (s, 2H). ¹³C NMR (CD₂Cl₂,

300.0K): d: 164.7 [C]; 157.2 [C, d, J: 249 Hz]; 147.3 [C];

136.0 [CH, d, J: 25 Hz]; 125.6 [CH, d, J: 20 Hz]; 115.1

[CH]; 43.4 [CH₂].

2-Chloro-N-(2-(5-chloro)pyridinyl)acetamide (10b). The

procedure described above was used with 5.0 g of 8b.

Elution with CH₂Cl₂/EtOAc (90/10 to 50/50 v/v) gave

3.33 g of the desired product as a white solid (42%). R_f

1

(Heptane/EtOAc: 60/40 v/v): 0.55. H NMR (CD₂Cl₂,

300.0K): d: 8.88 (b, 1H); 8.27 (bd, J <1.0 Hz, 1H); 8.16

(d, J: 9.0 Hz, 1H); 7.71 (dd, J: 2.0 and 9.0 Hz, 1H); 4.21

(s, 2H). ¹³C NMR (CD₂Cl₂, 300.0K): d: 164.9 [C]; 149.4

[C]; 147.1 [CH]; 138.5 [CH]; 127.9 [C]; 114.9 [CH]; 43.4

[CH₂].

2-[1-(4-(2-Methoxyphenyl)piperazinyl]-N-(2-(6-ﬂuoro)pyr-

idinyl)acetamide (12a). The procedure described above

was used with 2.76 g of 9a. Elution with heptane/EtOAc

(50/50 v/v) gave 4.29 g of the desired product as a white

1

2-Chloro-N-(2-(5-bromo)pyridinyl)acetamide (10c). The

procedure described above was used with 1.0 g of 8c.

Elution with CH₂Cl₂/EtOAc (90/10 to 50/50 v/v) gave

1.2 g of the desired product as a yellow oil (81%). R_f

solid (85%). R_f(heptane/EtOAc: 50/50 v/v): 0.20. H

NMR (CD₂Cl₂, 300.0K): d: 9.55 (b, 1H); 8.11 (dd, J: 2.1

and 6.5 Hz, 1H); 7.79 (q, J: 7.2 Hz, 1H); 7.03–6.82 (4H);

6.66 (dd, J: 1.7 and 6.7 Hz, 1H); 3.84 (s, 3H); 3.21 (s,

2H); 3.15 (b, 4H); 2.77 (b, 4H). ¹³C NMR (CD₂Cl₂,

300.0K): d: 169.9 [C]; 162.8 [C, d, J: 238 Hz]; 153.2 [C];

150.3 [C, d, J: 14 Hz]; 143.9 [CH, d, J: 7 Hz]; 142.0 [C];

124.0 [C]; 123.6 [CH]; 121.7 [CH]; 119.1 [CH]; 112.3

[CH]; 104.7 [CH, d, J: 36 Hz]; 62.9 [CH₂]; 56.0 [CH₃];

54.9 [2 ꢂ CH₂]; 51.3 [2 ꢂ CH₂].

1

(EtOAc/Heptane: 50/50 v/v): 0.55. H NMR (CD₂Cl₂,

300.0K): d: 8.80 (b, 1H); 8.37 (d, J <1.0 Hz, 1H); 8.11

(d, J: 9.0 Hz, 1H); 7.84 (dd, J: 2.0 and 9 Hz, 1H); 4.20 (s,

2H). ¹³C NMR (CD₂Cl₂, 300.0K): d: 179.9 [C]; 164.9

[C]; 149.4 [CH]; 141.2 [CH]; 115.8 [C]; 115.4 [CH]; 43.4

[CH₂].

M. Karramkam et al. / Bioorg. Med. Chem. 11 (2003) 2769–2782

2777

2-[1-(4-(2-Methoxyphenyl)piperazinyl]-N-(2-(6-chloro)pyr-

idinyl)acetamide (12b). The procedure described above

was used with 1.52 g of 9b. Elution with heptane/EtOAc

(50/50 v/v) gave 2.15 g of the desired product as a white

(b, 2H); 7.67 (dd, J: 2.0 and 9.0 Hz, 1H); 7.05–6.85 (4H);

3.82 (s, 3H); 3.19 (s, 2H); 3.13 (b, 4H); 2.78 (b, 4H). ¹³C

NMR (CD₂Cl₂, 300.0K): d: 169.4 [C]; 152.8 [C]; 150.0

[C]; 147.0 [CH]; 141.7 [C]; 138.1 [CH]; 126.8 [C]; 123.2

[CH]; 121.3 [CH]; 118.6 [CH]; 114.6 [CH]; 111.9 [CH];

62.5 [CH₂]; 55.7 [CH₃]; 54.2 [2 ꢂ CH₂]; 51.0 [2 ꢂ CH₂].

1

solid (80%). R_f(heptane/EtOAc: 50/50 v/v): 0.25. H

NMR (CD₂Cl₂, 300.0K): d: 9.62 (b, 1H); 8.19 (d, J:

6.0 Hz, 1H); 7.65 (t, J: 9.0 Hz, 1H); 7.03 (d, J: 9.0 Hz,

1H); 7.02–6.82 (4H); 3.82 (s, 3H); 3.20 (s, 2H); 3.16 (b,

4H); 2.76 (b, 4H). ¹³C NMR (CD₂Cl₂, 300.0K): d: 169.6

[C]; 152.9 [C]; 151.6 [C]; 149.4 [C]; 141.7 [C]; 141.3 [CH];

123.3 [CH]; 121.5 [CH]; 119.9 [CH]; 118.8 [CH]; 112.2

[CH]; 112.0 [CH]; 62.7 [CH₂]; 55.7 [CH₃]; 54.3 [2 ꢂ

CH₂]; 51.0 [2 ꢂ CH₂].

2-[1-(4-(2-Methoxyphenyl)piperazinyl]-N-(2-(5-bromo)pyr-

idinyl)acetamide (13c). The procedure described above

was used with 1.51 g of 10c. Elution with heptane/

EtOAc (50/50 v/v) gave 1.37 g of the desired product as

a yellow oil (83%). R_f(heptane/EtOAc: 50/50 v/v): 0.35.

¹H NMR (CD₂Cl₂, 300.0K): d: 9.65 (b, 1H); 8.34 (d, J:

2.0 Hz, 1H); 8.18 (d, J: 9.0 Hz, 1H); 7.82 (dd, J: 2.0 and

9.0 Hz, 1H); 7.05–6.85 (4H); 3.82 (s, 3H); 3.20 (s, 2H);

3.13 (b, 4H); 2.78 (b, 4H). ¹³C NMR (CD₂Cl₂, 300.0K):

d: 169.5 [C]; 152.8 [C]; 150.4 [C]; 149.2 [CH]; 141.6 [C];

140.9 [CH]; 123.2 [CH]; 121.3 [CH]; 118.6 [CH]; 115.2

[CH]; 114.7 [C]; 111.9 [CH]; 62.5 [CH₂]; 55.7 [CH₃]; 54.2

[2 ꢂ CH₂]; 51.0 [2 ꢂ CH₂].

2-[1-(4-(2-Methoxyphenyl)piperazinyl]-N-(2-(6-bromo)pyr-

idinyl)acetamide (12c). The procedure described above

was used with 2.44 g of 9c. Elution with heptane/EtOAc

(50/50 v/v) gave 3.48 g of the desired product as a white

1

solid (91%). R_f(heptane/EtOAc: 50/50 v/v): 0.25. H

NMR (CD₂Cl₂, 300.0K): d: 9.61 (b, 1H); 8.19 (d, J:

9.0 Hz, 1H); 7.56 (t, J: 9.0 Hz, 1H); 7.21 (d, J: 9.0 Hz,

1H); 7.02–6.82 (4H); 3.82 (s, 3H); 3.20 (s, 2H); 3.15 (b,

4H); 2.75 (b, 4H). ¹³C NMR (CD₂Cl₂, 300.0K): d: 169.0

[C]; 153.1 [C]; 152.0 [C]; 141.9 [C]; 141.2 [CH]; 140.1 [C];

124.1 [CH]; 123.5 [CH]; 121.6 [CH]; 119.0 [CH]; 112.7

[CH]; 112.2 [CH]; 62.9 [CH₂]; 55.9 [CH₃]; 54.0 [2 ꢂ

CH₂]; 51.0 [2 ꢂ CH₂].

2-[1-(4-(2-Methoxyphenyl)piperazinyl]-N-(2-(5-nitro)pyr-

idinyl)acetamide (13d). The procedure described above

was used with 0.89 g of 10d. Elution with heptane/

EtOAc (50/50 v/v) gave 1.10 g of the desired product as

a yellow solid (71%). R_f(heptane/EtOAc: 50/50 v/v):

0.30. ¹H NMR (CD₂Cl₂, 300.0K): d: 10.00 (b, 1H); 9.15

(s, 1H); 8.55–8.40 (b, 2H); 7.05–6.85 (4H); 3.84 (s, 3H);

3.28 (s, 2H); 3.17 (b, 4H); 2.82 (b, 4H). ¹³C NMR

(CD₂Cl₂, 300.0K): d: 170.2 [C]; 155.6 [C]; 152.9 [C];

145.2 [CH]; 141.6 [C]; 141.0 [C]; 134.3 [CH]; 123.4 [CH];

121.4 [CH]; 118.7 [CH]; 113.0 [CH]; 112.0 [CH]; 62.5

[CH₂]; 55.7 [CH₃]; 54.3 [2 ꢂ CH₂]; 51.0 [2 ꢂ CH₂].

2-[1-(4-(2-Methoxyphenyl)piperazinyl]-N-(2-(6-nitro)pyr-

idinyl)acetamide (12d). The procedure described above

was used with 4.00 g of 9d. Elution with heptane/EtOAc

(50/50 v/v) gave 6.13 g of the desired product as a white

1

solid (89%). R_f(heptane/EtOAc: 50/50 v/v): 0.20. H

NMR (CD₂Cl₂, 300.0K): d: 9.80 (b, 1H); 8.63 (d, J:

9.0 Hz, 1H); 8.02 (t, J: 9.0 Hz, 1H); 7.92 (d, J: 9.0 Hz,

1H); 7.02–6.82 (4H); 3.83 (s, 3H); 3.26 (s, 2H); 3.16 (b,

4H); 2.79 (b, 4H). ¹³C NMR (CD₂Cl₂, 300.0K): d: 170.1

[C]; 155.4 [C]; 152.8 [C]; 150.8 [C]; 142.2 [CH]; 141.5 [C];

123.2 [CH]; 121.3 [CH]; 119.6 [CH]; 118.7 [CH]; 113.4

[CH]; 111.9 [CH]; 62.6 [CH₂]; 55.6 [CH₃]; 54.5 [2 ꢂ

CH₂]; 52.8 [2 ꢂ CH₂].

General procedure: 1-(2-methoxyphenyl)-4-(2-(2-(halo)-

aminopyridinyl)-ethyl)piperazines (14a–c and 14a–c).

To 5.0 mmol of the appropriate 2-[1-(4-(2-methoxy-

phenyl)piperazinyl]-N-(2-(halo)pyridinyl)acetamide (12a–c

or 13a–c) dissolved in 150 mL of dry THF, was slowly

added under N₂570 mg of LiAlH₄(15.0 mmol, 3 equiv).

The reaction mixture was stirred at room temperature

for 3 h. The reaction was then stopped by careful addi-

tion of ice and 10% aq NaOH. The mixture was stirred

at room temperature for another 30 min. The precipitate

was ﬁltered oﬀ and the ﬁltrate was extracted with ethyl

acetate. The organic layers were combined, dried over

Na₂SO₄, ﬁltered and concentrated. The residue was

chromatographed on silica gel.

2-[1-(4-(2-Methoxyphenyl)piperazinyl]-N-(2-(5-ﬂuoro)pyr-

idinyl)acetamide (13a). The procedure described above

was used with 1.26 g of 10a. Elution with heptane/

EtOAc (50/50 v/v) gave 1.77 g of the desired product as

a clear oil (77%). R_f(heptane/EtOAc: 50/50 v/v): 0.30.

¹H NMR (CD₂Cl₂, 300.0K): d: 9.60 (b, 1H); 8.25 (dd, J:

4.0 and 9.0 Hz, 1H); 8.14 (bd, J <2.0 Hz, 1H); 7.44 (dt,

J: 2.0 and 9.0 Hz, 1H); 7.05–6.85 (4H); 3.82 (s, 3H); 3.19

(s, 2H); 3.14 (b, 4H); 2.78 (b, 4H). ¹³C NMR (CD₂Cl₂,

300.0K): d: 169.1 [C]; 156.8 [C, d, J: 249 Hz]; 152.9 [C];

148.0 [C]; 141.7 [C]; 135.7 [CH, d, J: 26 Hz]; 125.3 [CH,

d, J: 19 Hz]; 123.3 [CH]; 121.4 [CH]; 118.7 [CH]; 114.7

[CH]; 112.0 [CH]; 62.5 [CH₂]; 55.7 [CH₃]; 54.3 [2 ꢂ

CH₂]; 51.0 [2 ꢂ CH₂].

1-(2-Methoxyphenyl)-4-(2-(2-(6-ﬂuoro)aminopyridinyl)-

ethyl)piperazine (14a). The procedure described above

was used with 2.0 g 12a. Elution with heptane/EtOAc

(60/40 to 10/90 v/v) gave 1.00 g of the desired product as

a yellow solid (52%). R_f(heptane/EtOAc: 10/90 v/v):

1

0.20. H NMR (CD₂Cl₂, 300.0K): d: 7.47 (t, J: 7.4 Hz,

1H); 7.02–6.82 (4H); 6.25 (dd, J: 2.4 and 7.8 Hz, 1H);

6.10 (dd, J: 2.3 and 8.0 Hz, 1H); 5.33 (b, 1H); 3.83 (s,

3H); 3.36 (q, J: 6.0 Hz, 2H); 3.07 (b, 4H); 2.66 (b, 6H).

¹³C NMR (CD₂Cl₂, 300.0K): d: 163.8 [C, d, J: 234 Hz];

158.8 [C, d, J: 17 Hz]; 152.8 [C]; 142.0 [C]; 141.5 [CH, d,

J: 7 Hz]; 123.0 [CH]; 121.3 [CH]; 118.5 [CH]; 111.9

[CH]; 103.9 [CH]; 95.4 [CH, d, J: 37 Hz]; 57.0 [CH₂];

55.6 [CH₃]; 53.8 [2 ꢂ CH₂]; 51.0 [2 ꢂ CH₂]; 39.3 [CH₂].

2-[1-(4-(2-Methoxyphenyl)piperazinyl]-N-(2-(5-chloro)pyr-

idinyl)acetamide (13b). The procedure described above

was used with 3.20 g of 10b. Elution with heptane/

EtOAc (50/50 v/v) gave 5.04 g of the desired product as

a yellow oil (90%). R_f(heptane/EtOAc: 50/50 v/v): 0.35.

¹H NMR (CD₂Cl₂, 300.0K): d: 9.66 (b, 1H); 8.30–8.15

2778

M. Karramkam et al. / Bioorg. Med. Chem. 11 (2003) 2769–2782

1

1-(2-Methoxyphenyl)-4-(2-(2-(6-chloro)aminopyridinyl)-

ethyl)piperazine (14b). The procedure described above

was used with 0.20 g of 12b. Elution with heptane/

EtOAc (60/40 to 10/90 v/v) gave 0.12 g of the desired

product as a yellow solid (62%). R_f(heptane/EtOAc:

10/90 v/v): 0.20. H NMR (CD₂Cl₂, 300.0K): d: 8.08

(bd, J: 2.0 Hz, 1H); 7.44 (dd, J: 2.0 and 9.0 Hz, 1H); 7.05–

6.85 (4H); 6.33 (d, J: 9.0 Hz, 1H); 5.23 (b, 1H); 3.81 (s,

3H); 3.33 (q, J: 6.0 Hz, 2H); 3.05 (b, 4H); 2.65 (b, 6H).

¹³C NMR (CD₂Cl₂, 300.0K): d: 157.9 [C]; 152.8 [C];

148.9 [CH]; 142.0 [C]; 139.6 [CH]; 122.9 [CH]; 121.3

[CH]; 118.5 [CH]; 111.9 [CH]; 109.0 [CH]; 106.8 [C];

57.0 [CH₂]; 55.6 [CH₃]; 53.6 [2 ꢂ CH₂]; 50.9 [2 ꢂ CH₂];

38.9 [CH₂].

1

10/90 v/v): 0.15. H NMR (CD₂Cl₂, 300.0K): d: 7.31 (t,

J: 9.0 Hz, 1H); 7.00–6.81 (4H); 6.97 (m, 4H); 6.51 (d, J:

9.0 Hz, 1H); 6.28 (d, J: 9.0 Hz, 1H); 5.37 (b, 1H); 3.80 (s,

3H); 3.34 (q, J: 6.0 Hz, 2H); 3.04 (b, 4H); 2.62 (b, 6H).

¹³C NMR (CD₂Cl₂, 300.0K): d: 159.3 [C]; 152.8 [C];

149.9 [C]; 142.0 [C]; 139.8 [CH]; 123.0 [CH]; 121.3 [CH];

118.5 [CH]; 111.9 [CH]; 111.6 [CH]; 105.3 [CH]; 56.9

[CH₂]; 55.6 [CH₃]; 54.2 [2 ꢂ CH₂]; 50.9 [2 ꢂ CH₂]; 38.8

[CH₂].

1-(2-Chloro-ethyl)-4-(2-methoxy-phenyl)-piperazine (16).

To a dry acetonitrile solution (30 mL) containing 1-(2-

methoxyphenyl)piperazine (11, 4.08 g, 21.28 mmol,

1 equiv) and triethylamine (3 mL, 21.28 mmol, 1 equiv)

were added dropwise an acetonitrile solution (10 mL)

containing 2-chloroethyl p-toluenesulfonate (25 g,

106.4 mmol, 5 equiv). The reaction mixture was stirred

at room temperature for 40 h and then concentrated.

The residue was diluted with 50 mL of water and was

extracted with dichloromethane. The organic layers

were combined, washed with water and brine, dried

over Na₂SO₄, ﬁltered and concentrated. The residue was

chromatographed on silica gel. Elution with heptane/

EtOAc (80/20 to 50/50 v/v) gave 1.45 g of the desired

product as a yellow oil (27%). R_f(heptane/EtOAc: 50/

1-(2-Methoxyphenyl)-4-(2-(2-(6-bromo)aminopyridinyl)-

ethyl)piperazine (14c). The procedure described above

was used with 2.0 g of 12c. Elution with heptane/EtOAc

(60/40 to 10/90 v/v) gave 1.38 g of the desired product as

a yellow solid (72%). R_f(heptane/EtOAc: 10/90 v/v):

1

0.15. H NMR (CD₂Cl₂, 300.0K): d: 7.23 (t, J: 9.0 Hz,

1H); 7.00–6.81 (4H); 6.67 (d, J: 9.0 Hz, 1H); 6.33 (d, J:

9.0 Hz, 1H); 5.35 (b, 1H); 3.82 (s, 3H); 3.35 (q, J: 6.0 Hz,

2H); 3.05 (b, 4H); 2.67 (b, 6H). ¹³C NMR (CD₂Cl₂,

300.0K): d: 159.4 [C]; 152.8 [C]; 142.0 [C]; 140.6 [C];

139.6 [CH]; 123.0 [CH]; 121.3 [CH]; 118.5 [CH]; 115.5

[CH]; 111.9 [CH]; 105.6 [CH]; 56.9 [CH₂]; 55.6 [CH₃];

53.8 [2 ꢂ CH₂]; 50.8 [2 ꢂ CH₂]; 38.7 [CH₂].

1

50 v/v): 0.40. H NMR (CD₂Cl₂, 300.0K): d: 7.00–6.80

(4H); 3.82 (s, 3H); 3.62 (t, J: 6.0 Hz, 2H); 3.04 (b, 4H);

2.76 (t, J: 6.0 Hz, 2H); 2.65 (b, 4H). ¹³C NMR (CDCl₃,

300.0K): d: 152.9 [C]; 142.0 [C]; 123.1 [CH]; 121.4 [CH];

118.6 [CH]; 111.9 [CH]; 60.3 [CH₂]; 55.7 [CH₃]; 53.9 [2

ꢂ CH₂]; 51.0 [2 ꢂ CH₂]; 41.8 [CH₂].

1-(2-Methoxyphenyl)-4-(2-(2-(5-ﬂuoro)aminopyridinyl)-

ethyl)piperazine (15a). The procedure described above

was used with 1.7 g of 13a. Elution with heptane/EtOAc

(60/40 to 10/90 v/v) gave 0.85 g of the desired product as

a yellow solid (51%). R_f(heptane/EtOAc: 10/90 v/v):

General procedure: 1-(2-Methoxyphenyl)-4-(2-(2-(nitro)-

aminopyridinyl)-ethyl)piperazines (14d and 15d). To a

solution of 2.0 mmol of the appropriate 2-amino-nitro-

pyridine (7d or 8d) in 20 mL of acetonitrile were added

510 mg of 1-(2-chloro-ethyl)-4-(2-methoxy-phenyl)-piper-

azine (16, 2.0 mmol, 1 equiv) and 0.418 mL of triethyla-

mine (3.0 mmol, 1.5 equiv). The reaction mixture was

reﬂuxed for 24 to 48 h and then concentrated. The resi-

due was diluted with 10 mL of water and was extracted

with dichloromethane. The organic layers were com-

bined, washed with water and brine, dried over Na₂SO₄,

ﬁltered and concentrated. The residue was chromato-

graphed on silica gel.

1

0.20. H NMR (CD₂Cl₂, 300.0K): d: 7.92 (d, J: 2 Hz,

1H); 7.17 (dt, J: 3.0 and 9.0 Hz, 1H); 7.05–6.85 (4H);

6.35 (dd, J: 5.0 and 9.0 Hz, 1H); 5.08 (b, 1H); 3.81 (s,

3H); 3.32 (bq, J: 5.0 Hz, 2H); 3.05 (b, 4H); 2.63 (b, 6H).

¹³C NMR (CD₂Cl₂, 300.0K): d: 156.3 [C]; 153.7 [C, d, J:

239 Hz]; 152.8 [C]; 142.1 [C]; 134.7 [CH, d, J: 24 Hz];

125.3 [CH, d, J: 20 Hz]; 123.0 [CH]; 121.3 [CH]; 118.5

[CH]; 111.9 [CH]; 107.7 [CH]; 57.2 [CH₂]; 55.6 [CH₃];

53.6 [2 ꢂ CH₂]; 51.0 [2 ꢂ CH₂]; 39.4 [CH₂].

1-(2-Methoxyphenyl)-4-(2-(2-(5-chloro)aminopyridinyl)-

ethyl)piperazine (15b). The procedure described above

was used with 0.5 g of 13b. Elution with heptane/EtOAc

(60/40 to 10/90 v/v) gave 0.35 g of the desired product as

a yellow solid (73%). R_f(heptane/EtOAc: 10/90 v/v):

1-(2-Methoxyphenyl)-4-(2-(2-(6-nitro)aminopyridinyl)-

ethyl)piperazine (14d). The procedure described above

was used with 0.36 mg of 2-amino-6-nitropyridine (7d).

Elution with heptane/EtOAc (50/50–10/90 v/v) gave

0.09 g of the desired product as a yellow solid (10%). R_f

1

0.20. H NMR (CD₂Cl₂, 300.0K): d: 7.99 (s, 1H); 7.34

(dd, J: 2.0 and 8.5 Hz, 1H); 7.05–6.85 (4H); 6.35 (d, J:

8.5 Hz, 1H); 5.20 (b, 1H); 3.81 (s, 3H); 3.33 (bq, J:

5.0 Hz, 2H); 3.05 (b, 4H); 2.63 (b, 6H). ¹³C NMR

(CD₂Cl₂, 300.0K): d: 157.7 [C]; 152.8 [C]; 146.7 [CH];

142.0 [C]; 137.1 [CH]; 122.9 [CH]; 121.3[CH]; 119.4 [C];

118.5 [CH]; 111.9 [CH]; 108.3 [CH]; 57.0 [CH₂]; 55.6

[CH₃]; 53.6 [2 ꢂ CH₂]; 51.0 [2 ꢂ CH₂]; 39.0 [CH₂].

1

(heptane/EtOAc: 50/50 v/v): 0.15. H NMR (CD₂Cl₂,

300.0K): d: 7.63 (t, J: 8.0 Hz, 1H); 7.40 (d, J: 7.9 Hz,

1H); 7.00–6.81 (4H); 6.74 (d, J: 8.0 Hz, 1H); 5.75 (b,

1H); 3.84 (s, 3H); 3.48 (q, J: 6.0 Hz, 2H); 3.08 (b, 4H);

2.70 (b, 6H). ¹³C NMR (CDCl₃, 300.0K): d: 158.3 [C];

156.6 [C]; 152.7 [C]; 141.9 [C]; 139.8 [CH]; 122.9 [CH];

121.2 [CH]; 118.4 [CH]; 113.4 [CH]; 111.8 [CH]; 105.6

[CH]; 56.7 [CH₂]; 55.6 [CH₃]; 53.4 [2 ꢂ CH₂]; 50.8 [2 ꢂ

CH₂]; 38.6 [CH₂].

1-(2-Methoxyphenyl)-4-(2-(2-(5-bromo)aminopyridinyl)-

ethyl)piperazine (15c). The procedure described above

was used with 1.37 g of 13c. Elution with heptane/

EtOAc (60/40 to 10/90 v/v) gave 0.79 g of the desired

product as a yellow solid (60%). R_f(heptane/EtOAc:

1-(2-Methoxyphenyl)-4-(2-(2-(5-nitro)aminopyridinyl)-

ethyl)piperazine (15d). The procedure described above

M. Karramkam et al. / Bioorg. Med. Chem. 11 (2003) 2769–2782

2779

was used with 0.30 mg of 2-amino-5-nitropyridine (8d).

Elution with heptane/EtOAc (50/50 to 10/90 v/v) gave

0.11 g of the desired product as a yellow solid (17%). R_f

43.0 [CH]; 30.1 [2 ꢂ CH₂]; 26.2 [CH₂]; 26.1 [2 ꢂ CH₂].

MS: 457 [M+H⁺]; 459 [M+H⁺].

1

(heptane/EtOAc: 50/50 v/v): 0.15. H NMR (CD₂Cl₂,

N-(2-(1-(4-(2-Methoxyphenyl)piperazinyl)ethyl))-N-(2-

(6-bromo)pyridinyl)cyclohexane carboxamide (5c). The

procedure described above was used with 510 mg of 14c.

Elution with heptane/EtOAc (80/20 to 50/50 v/v) gave

590 mg of the desired product as a yellow oil (91%). R_f

(heptane/EtOAc: 20/80 v/v): 0.50. Rt (HPLC A):

300.0K): d: 8.97 (d, J: 6.0 Hz, 1H); 8.18 (td, J: 2.0 and

6.0 Hz, 1H); 7.05–6.85 (4H); 6.37 (d, J: 7.0 Hz, 1H); 6.16

(b, 1H); 3.84 (s, 3H); 3.51 (b, 2H); 3.07 (b, 4H); 2.72 (b,

6H). ¹³C NMR (CDCl₃, 300.0K): d: 161.1 [C]; 152.6 [C];

147.1 [CH]; 141.7 [C]; 135.7 [C]; 132.7 [CH]; 122.8 [CH];

121.1 [CH]; 118.3 [CH]; 111.7 [2 ꢂ CH]; 56.3 [CH₂]; 55.4

[CH₃]; 53.3 [2 ꢂ CH₂]; 50.8 [2 ꢂ CH₂]; 38.6 [CH₂].

1

14.0 min. Rt (HPLC C): 7.37 min. H NMR (CD₂Cl₂,

300.0K): d: 7.57 (t, J: 9.0 Hz, 1H); 7.35 (d, J: 9.0 Hz,

1H); 7.31 (d, J: 9.0 Hz, 1H); 7.01–6.80 (4H); 3.99 (t, J:

9.0 Hz, 2H); 3.77 (s, 3H); 2.93 (b, 4H); 2.59 (b, 6H); 2.40

(t, J: 9.0 Hz, 1H); 1.90–1.05 (10H). ¹³C NMR (CD₂Cl₂,

300.0K): d: 176.5 [C]; 156.1 [C]; 152.6 [C]; 141.7 [C];

140.3 [CH]; 140.2 [C]; 125.8 [CH]; 122.8 [CH]; 121.2

[CH]; 120.1 [CH]; 118.3 [CH]; 111.8 [CH]; 56.7 [CH₂];

55.5 [CH₃]; 53.5 [2 ꢂ CH₂]; 50.5 [2 ꢂ CH₂]; 45.1 [CH₂];

42.9 [CH]; 30.0 [2 ꢂ CH₂]; 26.3 [CH₂]; 26.2 [2 ꢂ CH₂].

MS: 501 [M+H⁺]; 503 [M+H⁺].

General procedure: N-(2-(1-(4-(2-methoxyphenyl)piper-

azinyl)ethyl))-N-(2-pyridinyl)cyclohexane carboxamide

(5a–d and 6a–d). To a solution of 1.0 mmol of the

appropriate 1-(2-methoxyphenyl)-4-(2-(2-aminopyridinyl)-

ethyl)piperazine (14a–d or 15a–d) in 50 mL of dichloro-

methane were added dropwise cyclohexanecarbonyl

chloride (0.200 mL, 1.5 mmol, 1.5 equiv) and triethyla-

mine (0.210 mL, 1.5 mmol, 1.5 equiv). The reaction

mixture was stirred at room temperature for 48 h. The

reaction was then stopped by addition of 10% aq

NaHCO₃. The organic layer was separated and the

aqueous layer was extracted twice with dichloro-

methane. The organic layers were combined, washed

once with water and brine, dried over Na₂SO₄, ﬁltered

and concentrated. The residue was chromatographed on

silica gel.

N-(2-(1-(4-(2-Methoxyphenyl)piperazinyl)ethyl))-N-(2-

(6-nitro)pyridinyl)cyclohexane carboxamide (5d). The

procedure described above was used with 88 mg of 14d.

Elution with heptane/EtOAc (80/20 to 50/50 v/v) gave

80 mg of the desired product as a yellow oil (68%). R_f

(heptane/EtOAc: 20/80 v/v): 0.50. R_f(EtOAc): 0.6. Rt

(HPLC A): 9.0 min. Rt (HPLC B): 12.5 min. Rt (HPLC

1

C): 5.09 min. H NMR (CD₂Cl₂, 300.0K): d: 8.05 (b,

N-(2-(1-(4-(2-Methoxyphenyl)piperazinyl)ethyl))-N-(2-

(6-ﬂuoro)pyridinyl)cyclohexane carboxamide (5a). The

procedure described above was used with 106 mg of 14a.

Elution with heptane/EtOAc (80/20 to 50/50 v/v) gave

127 mg of the desired product as a yellow oil (90%). R_f

(heptane/EtOAc: 20/80 v/v): 0.50. Rt (HPLC A):

9.0 min. Rt (HPLC B): 9.0 min. Rt (HPLC C): 4.52 min.

¹H NMR (CD₂Cl₂, 300.0K): d: 7.84 (q, J: 9.0 Hz, 1H);

7.25 (dd, J: 1.8 and 6.0 Hz, 1H); 7.00–6.75 (5H); 3.97 (t,

J: 6.0 Hz, 2H); 3.79 (s, 3H); 2.96 (b, 4H); 2.60 (b, 6H);

2.41 (t, J: 9.0 Hz, 1H); 1.90–1.05 (10H). ¹³C NMR

(CD₂Cl₂, 300.0K): d: 177.0 [C]; 163.2 [C, d, J: 239 Hz];

155.0 [C, d, J: 13 Hz]; 153.3 [C]; 143.5 [CH, d, J: 8 Hz];

142.5 [C]; 123.5 [CH]; 121.8 [CH]; 119.5 [C]; 118.9 [CH];

112.5 [CH]; 107.8 [CH, d, J: 37 Hz]; 57.2 [CH₂]; 56.1

[CH₃]; 54.1 [2 ꢂ CH₂]; 51.3 [2 ꢂ CH₂]; 45.8 [CH₂]; 43.4

[CH]; 30.6 [2 ꢂ CH₂]; 26.9 [CH₂]; 26.8 [2 ꢂ CH₂]. MS:

441 [M+H⁺].

2H); 7.90 (dd, J: 1.9 and 6.4 Hz, 1H); 7.00–6.80 (4H);

4.14 (t, J: 6.0 Hz, 2H); 3.81 (s, 3H); 2.92 (b, 4H); 2.74 (b,

6H); 2.59 (t, J: 8.5 Hz, 1H); 1.90–1.05 (10H). ¹³C NMR

(CD₂Cl₂, 300.0K): d: 177.8 [C]; 155.9 [C]; 155.7 [C];

153.2 [C]; 142.1 [C]; 141.7 [CH]; 127.0 [CH]; 123.5 [CH];

121.7 [CH]; 118.9 [CH]; 115.1 [CH]; 112.3 [CH]; 58.6

[CH₂]; 56.1 [CH₃]; 54.2 [2 ꢂ CH₂]; 51.0 [2 ꢂ CH₂]; 45.5

[CH₂]; 43.6 [CH]; 30.6 [CH₂]; 26.6 [2 ꢂ CH₂]; 26.5

[CH₂]. MS: 468 [M+H⁺].

N-(2-(1-(4-(2-Methoxyphenyl)piperazinyl)ethyl))-N-(2-

(5-ﬂuoro)pyridinyl)cyclohexane carboxamide (6a). The

procedure described above was used with 840 mg of 15a.

Elution with heptane/EtOAc (80/20 to 50/50 v/v) gave

910 mg of the desired product as a yellow oil (81%). R_f

1

(heptane/EtOAc: 20/80 v/v): 0.50. H NMR (CD₂Cl₂,

300.0K): d: 8.35 (bd, J: 3.0 Hz, 1H); 7.49 (dt, J: 3.0 and

9.0 Hz, 1H); 7.37 (dd, J: 4.0 and 9.0 Hz, 1H); 7.05–6.85

(4H); 3.90 (t, J: 5.0 Hz, 2H); 3.80 (s, 3H); 2.95 (b, 4H);

2.55 (b, 6H); 2.19 (t, J: 7.0 Hz, 1H); 1.90–1.05 (10H).

¹³C NMR (CD₂Cl₂, 300.0K): d: 176.3 [C]; 158.4 [C, d, J:

254 Hz]; 152.8 [C]; 152.5 [C]; 142.0 [C]; 137.2 [CH, d, J:

24 Hz]; 125.4 [CH, d, J: 20 Hz]; 123.9 [CH]; 122.9 [CH];

121.3 [CH]; 118.4 [CH]; 111.9 [CH]; 56.6 [CH₂]; 55.6

[CH₃]; 53.8 [2 ꢂ CH₂]; 50.9 [2 ꢂ CH₂]; 45.4 [CH₂]; 42.7

[CH]; 29.9 [2 ꢂ CH₂]; 26.0 [CH₂]; 25.9 [2 ꢂ CH₂]. MS:

441 [M+H⁺].

N-(2-(1-(4-(2-Methoxyphenyl)piperazinyl)ethyl))-N-(2-

(6-chloro)pyridinyl)cyclohexane carboxamide (5b). The

procedure described above was used with 92 mg of 14b.

Elution with heptane/EtOAc (80/20 to 50/50 v/v) gave

100 mg of the desired product as a yellow oil (81%). R_f

(heptane/EtOAc: 20/80 v/v): 0.55. Rt (HPLC A):

1

12.0 min. Rt (HPLC C): 6.37 min. H NMR (CD₂Cl₂,

300.0K): d: 7.70 (t, J: 9.0 Hz, 1H); 7.27 (d, J: 9.0 Hz,

1H); 7.22 (d, J: 9.0 Hz, 1H); 7.02–6.82 (4H); 3.98 (t, J:

6.0 Hz, 2H); 3.80 (s, 3H); 2.93 (b, 4H); 2.58 (b, 6H); 2.35

(t, J: 9.0 Hz, 1H); 1.90–1.05 (10H). ¹³C NMR (CD₂Cl₂,

300.0K): d: 176.7 [C]; 156.2 [C]; 152.8 [C]; 150.1 [C];

142.0 [C]; 140.6 [CH]; 123.2 [CH]; 122.2 [CH]; 121.3

[CH]; 120.3 [CH]; 118.5 [CH]; 111.9 [CH]; 56.8 [CH₂];

55.6 [CH₃]; 53.8 [2 ꢂ CH₂]; 50.8 [2 ꢂ CH₂]; 45.3 [CH₂];

N-(2-(1-(4-(2-Methoxyphenyl)piperazinyl)ethyl))-N-(2-

(5-chloro)pyridinyl)cyclohexane carboxamide (6b). The

procedure described above was used with 335 mg of 15b.

Elution with heptane/EtOAc (80/20 to 50/50 v/v) gave

355 mg of the desired product as a yellow oil (81%). R_f

1

(heptane/EtOAc: 20/80 v/v): 0.50. H NMR (CD₂Cl₂,

2780

M. Karramkam et al. / Bioorg. Med. Chem. 11 (2003) 2769–2782

300.0K): d: 8.43 (bd, J: 2.0 Hz, 1H); 7.71 (dd, J: 3.0 and

9.0 Hz, 1H); 7.34 (d, J: 8.5 Hz, 1H); 7.05–6.85 (4H); 3.95

(bt, J: 5.0 Hz, 2H); 3.80 (s, 3H); 2.94 (b, 4H); 2.58 (b,

6H); 2.35 (t, J: 8.5 Hz, 1H); 1.90–1.05 (10H). ¹³C NMR

(CD₂Cl₂, 300.0K): d: 176.4 [C]; 154.7 [C]; 152.8 [C];

148.0 [CH]; 142.0 [C]; 138.0 [CH]; 130.0 [C]; 123.3 [CH];

122.9 [CH]; 121.3 [CH]; 118.4 [CH]; 111.9 [CH]; 56.7

[CH₂]; 55.6 [CH₃]; 53.8 [2 ꢂ CH₂]; 50.8 [2 ꢂ CH₂]; 45.3

[CH₂]; 42.8 [CH]; 30.0 [2 ꢂ CH₂]; 29.6 [CH₂]; 26.1

[CH₂]; 26.0 [2 ꢂ CH₂]. MS: 457 [M+H⁺]; 459 [M+H⁺].

no-carrier-added K[¹⁸F]F-K₂₂₂complex as a white semi-

solid residue.

If desired, the [¹⁸F]ﬂuoride ion production batch on the

cartridge can also be divided into 2–12 aliquots in order

to perform parallel syntheses. To do this, the [¹⁸F]ﬂuoride

ion is eluted from the resin using 1.0 mL of a 4.5 mg/mL

aqueous K₂CO₃solution into an empty Vacutainer¹

tube. In order to distribute equally this activity over n

tubes (Vacutainer¹tube, n=2–12), the quantity of

K₂CO₃was ﬁrstly adjusted to n times 4.5 mg with a

50.0 mg/mL aqueous K₂CO₃solution and secondly, the

total volume of the solution was adjusted to 2.0 mL with

water. This new aqueous [¹⁸F]ﬂuoride solution was then

equally distributed over the n tubes each containing

12.0–15.0 mg of Kryptoﬁx¹222 (K₂₂₂: 4,7,13,16,21,24-

hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane). Finally,

the volume of each fraction was adjusted to 1.0 mL

with water. The resulting solutions were then indepen-

dently gently concentrated to dryness at 145–150 ^ꢀC

under a nitrogen stream for 10 min to give no-carrier-

added K[¹⁸F]F-K₂₂₂complex as a white semi-solid

residue.

N-(2-(1-(4-(2-Methoxyphenyl)piperazinyl)ethyl))-N-(2-

(5-bromo)pyridinyl)cyclohexane carboxamide (6c). The

procedure described above was used with 738 mg of 15c.

Elution with heptane/EtOAc (80/20 to 50/50 v/v) gave

925 mg of the desired product as a yellow oil (98%). R_f

1

(heptane/EtOAc: 20/80 v/v): 0.50. H NMR (CD₂Cl₂,

300.0K): d : 8.54 (d, J <1.0 Hz, 1H); 7.85 (dd, J: 3.0 and

9.0 Hz, 1H); 7.27 (d, J: 9.0 Hz, 1H); 7.05–6.85 (4H); 3.96

(bt, J: 5.0 Hz, 2H); 3.80 (s, 3H); 2.94 (b, 4H); 2.59 (b,

6H); 2.35 (t, J: 7.5 Hz, 1H); 1.90–1.05 (10H). ¹³C NMR

(CD₂Cl₂, 300.0K): d: 176.4 [C]; 155.0 [C]; 152.8 [C];

150.2 [CH]; 141.9 [C]; 140.8 [CH]; 123.7 [CH]; 122.9

[CH]; 121.2 [CH]; 118.4 [CH]; 118.3 [C]; 111.9 [CH];

56.6 [CH₂]; 55.6 [CH₃]; 53.7 [2 ꢂ CH₂]; 50.7 [2 ꢂ CH₂];

45.2 [CH₂]; 42.7 [CH]; 30.0 [2 ꢂ CH₂]; 29.6 [CH₂]; 26.1

[CH₂]; 26.0 [2 ꢂ CH₂]. MS: 501 [M+H⁺]; 503 [M+H⁺].

6- and 5-[¹⁸F]ﬂuoropyridine derivatives: incorporation

studies with K[¹⁸F]F-K₂₂₂-complex

General procedure using conventional heating or micro-

wave activation in a non-sealed reactor. Freshly distilled

DMSO (600 mL) containing 2.0–6.0 mg of the precursor

for labelling 5b–d or 6b–d were directly added into the

Vacutainer¹tube containing the dried K[¹⁸F]F-K₂₂₂

complex. The tube (not sealed) was then placed in a

heating block (at 145 ^ꢀC for 1–30 min) or in a dedicated

microwave oven (at 100 W, for 1–3 min) without stirring

the contents. The reaction vessel was then cooled using

an ice-water bath and the remaining radioactivity was

measured; 90–95% of the initial radioactivity placed in

the vessel was still present. The resulting dark-coloured

reaction mixture was then analyzed by radio-

chromatography. The reaction yield was calculated

from the TLC-radiochromatogram and deﬁned as the

radioactivity area of the [¹⁸F]ﬂuoropyridine derivatives

over total ﬂuorine-18 radioactivity area ratio. (SiO₂-

TLC, eluent: EtOAc/MeOH: 90/10 v/v, R_f: 6- or 5-

[¹⁸F]ﬂuoro-WAY-100635 ([¹⁸F]5a/6a): 0.70 and R_f:

[¹⁸F]ﬂuoride ion: 0.0). Radiosynthesized 6-[¹⁸F]ﬂuoro-

WAY-100635 ([¹⁸F]5a) co-migrated with an authentic

sample of ﬂuorine-19-synthesized 5a; Concerning 5-

[¹⁸F]ﬂuoro-WAY-100635 ([¹⁸F]6a), no peak could be

detected at the R_fof ﬂuorine-19-synthesized 6a.

N-(2-(1-(4-(2-Methoxyphenyl)piperazinyl)ethyl))-N-(2-

(5-nitro)pyridinyl)cyclohexane carboxamide (6d). The

procedure described above was used with 114 mg of 15d.

Elution with heptane/EtOAc (80/20 to 50/50 v/v) gave

94 mg of the desired product as a yellow oil (63%). R_f

1

(heptane/EtOAc: 20/80 v/v): 0.45. H NMR (CD₂Cl₂,

300.0K): d: 9.24 (bd, J <1.5 Hz, 1H); 8.42 (dd, J: 2.0

and 6.0 Hz, 1H); 7.70 (d, J: 7.0 Hz, 1H); 7.05–6.85 (4H);

4.13 (t, J: 6.0 Hz, 2H); 3.81 (s, 3H); 2.93 (b, 4H); 2.71 (b,

6H); 2.25 (t, J: 8.0 Hz, 1H); 1.90–1.05 (10H). ¹³C NMR

(CD₂Cl₂, 300.0K): d: 177.4 [C]; 159.9 [C]; 152.4 [C];

144.2 [CH]; 141.4 [C]; 140.9 [C]; 132.5 [CH]; 122.6 [CH];

120.9 [CH]; 119.5 [CH]; 118.0 [CH]; 111.5 [CH]; 57.0

[CH₂]; 55.2 [CH₃]; 53.5 [2 ꢂ CH₂]; 50.4 [2 ꢂ CH₂]; 44.9

[CH₂]; 43.2 [CH]; 29.8 [2 ꢂ CH₂]; 25.8 [CH₂]; 25.7 [2 ꢂ

CH₂]. MS: 468 [M+H⁺].

Radiochemistry

Preparation of the K[¹⁸F]F-K₂₂₂-complex. In order to

recover and recycle the [¹⁸O]water target, the 2 mL of

aqueous [¹⁸F]ﬂuoride from the target holder were pas-

sed through an anion exchange resin (Sep-Pak¹Light

Waters Accell^TMPlus QMACartridge in the chloride

form, washed with 5 mL 1 M aq NaHCO₃and then

rinsed with 50 mL of water) by He pressure (1.5–2.0

General procedure using conventional heating in a sealed

reactor. The K[¹⁸F]F-K₂₂₂complex (Vacutainer¹tube)

was dissolved in 200 mL of a freshly distilled DMSO and

transferred to a 5 mL pyrex¹reaction vial containing

2.0–6.0 mg of the precursor for labelling (5b–d or 6b–d).

The evaporation tube was rinsed twice with 200 mL of

DMSO which was then added to the reaction mixture.

Resolubilization eﬃciencies were about 60–90% of the

original [¹⁸F]ﬂuoride ion. The reaction vial was then

tightly closed with a Teﬂon cap and heated in a heating

block (at 150–250 ^ꢀC, for 0–30 min) without stirring the

bar). He is blown through the column to extract the last

35,39

traces of [¹⁸O]water. See references

for more prac-

tical details. The [¹⁸F]ﬂuoride ion is then eluted from the

resin using 1.0 mL of a 4.5 mg/mL aqueous K₂CO₃

solution into a Vacutainer¹tube containing 12.0–

15.0 mg of Kryptoﬁx¹222 (K₂₂₂: 4,7,13,16,21,24-hex-

aoxa-1,10-diazabicyclo[8.8.8]hexacosane). The resulting

solution was then gently concentrated to dryness at

145–150 ^ꢀC under a nitrogen stream for 10 min to give

M. Karramkam et al. / Bioorg. Med. Chem. 11 (2003) 2769–2782

2781

contents. The remainder of the synthesis used the same

procedure as described above.

and radiochemically pure (retention time: 4.52 min). The

preparation was shown to be free of non-radioactive

precursor and radiochemically stable for at least 120 min.

N-(2-(1-(4-(2-Methoxyphenyl)piperazinyl)ethyl))-N-(2-

(6-[¹⁸F]ﬂuoro)pyridinyl)cyclohexane carboxamide or 6-

[¹⁸F]ﬂuoro-WAY-100635 ([¹⁸F]5a)

Acknowledgements

Procedure using the 6-bromo derivative 5c as precursor

for labelling. Freshly distilled DMSO (600 mL) contain-

ing 5.0 mg of the precursor for labelling 5c were directly

added into the Vacutainer¹tube containing the dried

K[¹⁸F]F-K₂₂₂complex. The tube (not sealed) was then

placed in a heating block (at 145 ^ꢀC for 10 min) or in a

dedicated microwave oven (at 100 W, for 3 min). The

reaction vessel was then cooled using an ice-water bath.

The resulting dark-coloured reaction mixture was dilu-

ted with 1 mL of water and transferred on a C18 Sep-

Pak cartridge (PrepSep^TMR-C18, Fisher Scientiﬁc). The

tube was rinsed twice with 1 mL of water, which was

also transferred and added to the diluted reaction mix-

ture on the cartridge. The whole was then passed

through the cartridge, which was then partially dried for

0.5 min by applying a nitrogen stream. At this stage, a

loss of the desired 6-[¹⁸F]ﬂuoropyridine derivative

[¹⁸F]5a could not be avoided and 20–30% of the radio-

tracer was found in the waste. The 6-[¹⁸F]ﬂuoro-WAY-

100635 ([¹⁸F]5a) was eluted from the cartridge with

3 mL of dichloromethane. Twice 1 mL of dichloro-

methane was used to wash the cartridge and to com-

pletely transfer [¹⁸F]5a (5–10% of the total radioactivity

amount engaged in the ﬂuorination process was left on

the cartridge). The mentioned dichloromethane solution

was concentrated to dryness (at 60–80 ^ꢀC under a gentle

nitrogen stream for 4–6 min). Finally, the residue was

redissolved in 1.0 mL of the HPLC solvent used for

puriﬁcation and the crude was injected onto HPLC.

Isocratic elution [HPLC A] gave pure labelled 6-

[¹⁸F]ﬂuoro-WAY-100635 ([¹⁸F]5a), retention time:

9.0 min.

The authors wish to thank the cyclotron operators Mr.

Daniel Gouel, Mr. Christophe Peronne and Mr. Chris-

tophe Lecheˆ ne for performing the irradiations, as well

as Ms Badia Amekraz (Laboratoire de Speciation des

Radionucleides et des Molecules, DEN/DPC/SECR,

CEA-Saclay, F-91191 Gif-sur-Yvette, France) for record-

ing the MS spectra.

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Article Doi

Synthesis of a [6-Pyridinyl-18F]-labelled fluoro derivative of WAY-100635 as a candidate radioligand for brain 5-HT1A receptor imaging with PET

DOI: 10.1016/S0968-0896(03)00225-6

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Full text of DOI:10.1016/S0968-0896(03)00225-6

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