174
J. Schmitz et al.: Allosteric Modulators of Muscarinic Receptors
procured by Mikrowellen-Laborsysteme (MWS, Leutkirch=
Germany). Weflon-tablets (PTFE with 10% graphite) were
used in apolar solvents, e.g. toluene.
room temperature the crystalline solid was filtered off and
recrystallized from ethanol to give 2.9g (54%) of fine yellow-
ish needles.
Preparation via the Conventional Route
The compounds 1c and 2b were synthesized convention-
ally according to Ref. [6], 4a according to Ref. [8], 1d and
3a according to Ref. [9], 1a, 1b, 2a, 3b, and 4b according to
Ref. [11] and compounds 5 and 6 according to Ref. [13].
Acknowledgements
Thanks are due to W. Lautenschl a¨ ger and his team from
Mikrowellen-Laborsysteme (MWS, Leutkirch=Germany) for
special equipment and technical support and the DFG (HO
1
367=7-3) for financial support.
Preparation via Microwave Heating
Synthesis of the Imides 1a, 1b, 1c, and 1d
References
A mixture of the appropriate anhydride (50 mmol), the cor-
responding primary amine (50 mmol), and a catalytic amount
of p-toluenesulfonic acid and two weflon-tablets (PTFE with
[
[
[
1] Ellis J (1997) Drug Dev Res 40: 193
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3] Birdsall NJ, Lazareno S (2005) Mini-Rev Med Chem 5:
ꢁ
1
0% graphite) were heated at 115 C in toluene by using a
5
23
ꢁ
water separator (ramp: 30 C=min, 800 W). When the reaction
was completed the solvent was evaporated and the obtained
crystals were washed several times with petroleum ether and
recrystallized from methanol.
[
4] Tu cˇ ek S, Mus ˘ı lkov a˘ J, Nedoma J, Pro sˇ ka S, Shelkovnikov
S, Vorl ˘ı cˇ ek J (1990) Mol Pharmacol 38: 674
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A (1992) Pharm Pharmacol Lett 2: 100
[
[
Synthesis of the Intermediate Compounds 2a and 2b
The corresponding imides 1b and 1c (10 mmol) were dissolved
in a fifteen fold excess of 1,6-dibromohexane (150mmol) and
stirred at 80 C (ramp: 20 C=min, 800 W). After cooling to
room temperature the obtained precipitate was filtered off and
washed with hot diethyl ether.
[
7] Bender W, Staudt M, Tr a¨ nkle C, Mohr K, Holzgrabe U
(2000) Life Sci 66: 1675
[8] Wassermann O (1970) Habilitationsschrift, University
of Kiel
[9] Muth M, Bender W, Scharfenstein O, Holzgrabe U,
Balatkova E, Tr a¨ nkle C, Mohr K (2003) J Med Chem
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4
10] Muth M, Sennwitz M, Mohr K, Holzgrabe U (2005)
J Med Chem 48: 2212
[11] Raasch A, Scharfenstein O, Tr a¨ nkle C, Holzgrabe U,
6: 1031
[
Synthesis of the Non-symmetrical Compounds 3a and 3b
The precursors 2a and 2b (10 mmol), 1a and a catalytic
3
amount of KI=K CO (1:1) were dissolved in 150 cm aceto-
2
3
ꢁ
ꢁ
Mohr K (2002) J Med Chem 45: 3809
12] Pick R, Duda-Johner S, Tr a¨ nkle C, Mohr K, Holzgrabe
U (2004) Monatsh Chem 135: 1539
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Tr a¨ nkle C (1994) J Med Chem 37: 1439
14] Kappe OC, Stadler A (2005) Microwaves in Organic and
Medicinal Chemistry. In: Mannhold R, Kubinyi G,
Folkers G (eds) Methods and Principles in Medicinal
Chemistry, vol 25. Wiley VCH, Weinheim
nitrile and heated to 90 C (ramp: 20 C=min, 800 W). After
cooling to room temperature the resulting precipitate was fil-
tered off and washed with acetonitrile and n-pentane.
[
[
[
Synthesis of the Symmetrical Compounds 4a and 4b
Two equivalents of the corresponding imides 1a and 1d
(
(
(
2mmol), respectively, and a catalytic amount of KI=K CO3
2
1:1) were dissolved in 1 equivalent of 1,6-dibromohexane
ꢁ
ꢁ
1mmol) and heated at 100 C (ramp: 20 C=min, 800 W).
[
[
15] Galema SA (1997) Chem Soc Rev 26: 233
16] Borah HN, Boruah RC, Sandhu JS (1998) J Chem Res
Syn 1: 272
After cooling to room temperature the obtained precipitate
was filtered off and washed with acetonitrile and n-pentane.
[
[
17] Kacprzak K (2003) Synth Commun 33: 1499
18] Habibi D, Marvi O (2006) Arkivoc 13: 8
0
(
E,E)-1-1 -(1,3-Propanediyl)bis[4-[[(2,6-
dichlorobenzyloxy)imino] methyl]pyridinium]
[19] Bogdal D, Pielichiowski J (1996) Synlett 9: 873
[20] Ju Y, Varma RS (2004) Green Chem 6: 219
[21] Vega JA, Vaquero JJ, Alvarez-Builla J, Ezquerra J,
Hamdouchi C (1999) Tetrahedron 55: 2317
[22] Lidstr o¨ m P, Tierney J, Wathey B, Westman J (2001)
Tetrahedron 57: 9225
dibromide (6, C H Br Cl N O )
2
9
26
2
4
4
2
Pyridine-4-carboxaldehyde
oxime 5 (4.0 g, 14.2mmol) and 1,3-dibromopropane (1.4g,
(E)-O-(2,6-dichlorobenzyl)-
3
.1 mmol) were dissolved in acetonitrile (70 cm ) and heated
7
at 85 C (ramp: 20 C=min, 800 W) for 3 h. After cooling to
ꢁ
ꢁ
¨
Verleger: Springer-Verlag GmbH, Sachsenplatz 4–6, 1201 Wien, Austria. – Herausgeber: Osterreichische Akademie der Wissenschaften, Dr.-Ignaz-Seipel-Platz 2,
¨
010 Wien, und Gesellschaft Osterreichischer Chemiker, Eschenbachgasse 9, 1010 Wien, Austria. – Redaktion: Getreidemarkt 9=163-OC, 1060 Wien, Austria. –
1
Satz und Umbruch: Thomson Press Ltd., Chennai, India. – Offsetdruck: Krips bv, Kaapweg 6, 7944 HV Meppel, The Netherlands. – Verlagsort: Wien. –
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