Synthesis of some new 4-substituted N-benzyl-piperidines

Article abstract of DOI:10.1081/SCC-120021515

Via Knoevenagel condensation of N-benzyl-4-piperidone with malononitrile some new 4-substituted N-benzyl-piperidines have been prepared. By means of these transformations an economic and large-scale synthesis of biologically important intermediate N-benzyl-piperidine-4-ethanol has been elaborated.

Full text of DOI:10.1081/SCC-120021515

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Synthesis of Some New 4-Substituted N-Benzyl-
piperidines
Gábor Dörnyei a , Mária Incze a , István Moldvai a & Csaba Szántay a
a Institute of Chemistry , Chemical Research Center , Hungarian Academy of Sciences ,
Pusztaszeri, Hungary
Published online: 17 Aug 2006.
To cite this article: Gábor Dörnyei , Mária Incze , István Moldvai & Csaba Szántay (2003) Synthesis of Some New 4-Substituted
N-Benzyl-piperidines, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 33:13, 2329-2338, DOI: 10.1081/SCC-120021515
To link to this article: http://dx.doi.org/10.1081/SCC-120021515
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 13, pp. 2329–2338, 2003
Synthesis of Some New
4-Substituted N-Benzyl-piperidines
*
Gabor Dornyei, Maria Incze, Istvan Moldvai,
and Csaba Szantay
Institute of Chemistry, Chemical Research Center,
Hungarian Academy of Sciences, Pusztaszeri, Hungary
ABSTRACT
Via Knoevenagel condensation of N-benzyl-4-piperidone with
malononitrile some new 4-substituted N-benzyl-piperidines have
been prepared. By means of these transformations an economic
and large-scale synthesis of biologically important intermediate N-
benzyl-piperidine-4-ethanol has been elaborated.
*Correspondence: Gabor Dornyei, Institute of Chemistry, Chemical Research
Center, Hungarian Academy of Sciences 1025 Budapest, Pusztaszeri ut 59-67,
Hungary; E-mail: gdornyei@chemres.hu.
2329
DOI: 10.1081/SCC-120021515
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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2330
Dornyei et al.
N-Benzyl-piperidine-4-acetates (e.g., 3) and N-benzyl-piperidine-4-
ethanol (4) are regarded as important intermediates in the synthesis of
biologically active 1,4-disubstituted piperidines.[1–5] In an attempt to find
an economic synthesis of the above intermediates, which can be easily
scaled up, the earlier methods, summarized by Gilligan et al.[2] have been
overviewed. An elegant and originally three-step method (phosphonate
condensation, catalytic reduction, and subsequent LAH reduction), mod-
ified and simplified by Dutta et al.,[4] was chosen to utilize. According to
thelattre authors N-benzyl-4-piperidone (1) condensed with triethyl
phosphonoacetate supplies the unsaturated ester (2) in 26% yield. They
omitted the catalytic hydrogenation step, and by a parallel reduction of
thedoublebond and thecarbonyl function in
2 with LiAlH4/THF
obtained the desired alcohol (4) in nearly quantitative yield.
Reproducing their experiments we succeeded to optimize the Wittig-
Homer condensation; the yield of the first step was enhanced over
90%. The LiAlH4 reduction of the unsaturated ester 2, however, gave
a mixture, in which the unsaturated alcohol (5) dominated, and the
desired N-benzyl-piperidine-4-ethanol (4) was only minor product.
Catalytic reduction of this mixture on Pd/C resulted in partial hydroge-
nolysis of the N-benzyl moiety, and a mixture, from which 4 could be
isolated only by chromatography and in poor yield, was obtained.
Similarly catalytic reduction of the unsaturated ester 2 on Pd/C was
accompanied by almost total debenzylation (6).

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4-Substituted N-Benzyl-piperidines
2331
Though the selective hydrogenolysis of the double bond of either
ester 2 or unsaturated ethanol 5 is expected to be realized on Adam’s
catalyst,[1] its realization in large scale would not be regarded an
economic solution. Therefore an alternative procedure was required to
elaborate.
Recalling our earlier method utilized for similar substitution of
quinolizidines during the synthesis of some alkaloids and alkaloid-like
compounds,[6–8] N-benzyl-4-piperidone (1) was reacted with malono-
nitrile. The exocyclic double bond of the unsaturated dinitrile (7),
obtained in almost quantitative yield, was reduced with NaBH4 in
MeOH/CH2Cl2. In theraection formation of dinitrile8
could be
detected primarily (TLC), however subsequently its transformation
into a new intermediate was observed. Earlier it was proven[6] in the
case of similar reactions that methanol addition onto one of the two
nitrile functions—activated by the presence of the other one—took
place, and dinitrile 8 was slowly transformed into iminoether 9. Whe n
intermediate iminoether 9, which provde to bestablein basic mdeia
(TLC), was treated with HCl in MeOH/H2O 10:1 without isolation,
cyanoester 10 was formed and isolated as hydrochloride salt. Thus
from unsaturated dinitrile 7 in a one-pot process cyanoester 10 could
beobtained in high (85%) yield.
It is worth to mention that saturated dinitrile 8 could beisolated and
characterized, when the NaBH4 reduction was performed in acidic media
(solvent: CH2Cl2–AcOH). On the other hand when into the solution of
iminoether 9 dry HCl gas was bubbled till pH 2, at the end of the one-pot
reaction cyanoamide 11 could beisolated. Hydrolysis of 10 or 11 in 20%
aqueous NaOH furnished the crystalline disodium salt of malonic acid
derivative (12).
Disodium salt 12 could be transformed into dimethyl malonate 13 by
treating with HCl/MeOH. On the other hand compound 12 afforded
methyl ester 15 in a two-step (decarboxylation, esterification) procedure.
Carboxylic acid 14—product of the first step—was preferably obtained
from ester 15 by aqueous hydrolysis. LiAlH4 reduction of ester 15
in THF provided us with N-benzyl-piperidine-4-ethanol (4) in nearly
quantitativeyield.
Finally our original aim to prepare N-benzyl-piperidine-4-ethanol (4)
was solved according to the above scheme (1!7!10!12!15!4) in a
55% overall yield. During the process several new products (7, 8, 10–13,
15) were synthesized and characterized.
This new approach outlined above possess four significant advan-
tages over the earlier ones; simplicity, inexpensity, high yields, and
capability for scaling up.

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2332
Dornyei et al.
EXPERIMENTAL
Melting points are uncorrected; IR spectra were recorded on a
1
Nicolet 205FT spectrophotometer. H and 13C NMR spectra were mea-
sured with a VARIAN VXR 200 instrument. Chemical shifts (ꢀ values)
are given relative to internal standard TMS. Abbreviations s, d, t, m, and
brs are used to designate singlet, doublet, triplet, multiplet, and broad
singlet, respectively. For TLC analyses MN Polygram SIL G/UV254
sheets were used.
N-Benzyl-piperidin-4-ylidene-malononitrile (7)
To thesolution of N-benzyl-4-piperidone (1; 18.93 g; 0.1 mol) in
dichloromethane (20 mL) freshly distilled malonitrile (6.61 g; 0.1 mol) dis-
solved in dichloromethane (15 mL) was added. The solution was stirred
at rt for 24 h. The mixture was dried from the water separated (Na2SO4),

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4-Substituted N-Benzyl-piperidines
2333
evaporated, and the residue crystallized from diethyl ether–hexane to
obtain unsaturated dinitrile 7 (21.5 g; 90%) as orangecrystals. M.p.
79–81ꢀC. Analysis: calculated C 75.92%, H 6.37%, N 17.71%; found
C 75.80%, H 6.50%, N 17.66%. IR (KBr): 2225 cmÀ1 (conj. CN).
1H NMR (CDCl3): 2.64 (4H, AB system, JAB ¼ 5.5 Hz, 3-H2 and 5-H2),
2.76 (4H, AB system, JAB ¼ 5.5 Hz, 2-H2 and 6-H2), 3.58 (2H, s, N-CH2-
Ph), 7.24–7.34 (5H, m, benzyl aromatic protons). 13C NMR (CDCl3):
34.00 (C3 þ C5), 52.87 (C2 þ C6), 61.42 (N-CH2-Ph), 83.33 (NC-C-
CN), 111.30 (CN), 127.44 (C40), 128.38 (C30), 128.80 (C20), 137.32 (Cl0),
181.34 (C4).
Methyl N-Benzyl-piperidin-4-yl-cyanoacetate (10)
Solution of unsaturated dinitrile 7 (23.73 g; 0.1 mol) in themixtureof
dichloromethane (100 mL) and methanol (200 mL) was cooled to 0–5ꢀC
with ice-water bath. Into this stirred solution NaBH4 (1.9 g; 0.05 mol) was
added in 8–10 portions during 1 h. Then the temperature of the mixture
was allowed to rt. After stirring for 1 h the reduction is complete (TLC,
eluent: hexane–EtOAc 1:1; Rf 8<Rf 7). Then the mixture was refluxed
for about 5 h. During this timethedinitrile
8 was transformed to
iminoether 9 (TLC, eluent: hexane–EtOAc 1:1; Rf 9 ꢁ Rf 8). The
cooled mixture was then acidified with 6 N HCl in MeOH–H2O 10:1
(pH 2), whereupon cyanoester 10 was formed (TLC, eluent: hexane–
EtOAc 1:1, Rf 10 ꢂRf 9). After evaporating the solvent the reminder
was dissolved in water (250 mL), cooled in ice bath and treated with cc
NH4OH (pH 8). The precipitate was extracted with CH2Cl2 (3 ꢃ 100 mL);
the combined organic phase was dried, acidified with 2 N HCl/MeOH
(pH 2), and evaporated in vacuo. The reminder was crystallized in
MeOH/diethyl ether to supply hydrochloride salt of cyanoester 10 as
colorless crystals. Yield: 26.3 g (85%), m.p. 187–188ꢀC.
For the purpose of characterization aliquot salt was transformed into
crystallinebas.e M.p. 82–83 ꢀC (ether–hexane). Analysis: calculated C
70.56%, H 7.40%, N 10.29%; found C 70.42%, H 7.55%, N 10.18%.
IR (KBr): 1735 and 1750 (CO ester), 2240 cmÀ1 (CN). 1H NMR (CDCl3):
1.65 (4H, m, 3- and 5-H2), 1.90–2.10 (3H, m, 2- and 6-Hax þ 4-H), 2.93
(2H, m, 2- and 6-Heq), 3.40 (1H, d, J ¼ 6.2 Hz, CO-CH-CN), 3.49 (2H, s,
N-CH2-Ph), 3.79 (3H, s, OCH3), 7.21–7.32 (5H, m, benzyl aromatic
protons). 13C NMR (CDCl3): 28.85 þ 30.06 (C3 þ C5), 37.08 (C4),
43.36 (CO-CH-CN), 52.74 (C2 þ C6), 53.25 (CH3O), 62.78 (N-CH2-
Ph), 115.22 (CN), 126.93 (C40), 128.10 (C30), 128.88 (C20), 138.07 (C10),
165.90 (CO).

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2334
Dornyei et al.
N-Benzyl-piperidin-4-yl-malonitrile (8)
Solution of unsaturated dinitrile 7 (2.4 g; 10 mmol) in themixtureof
dichloromethane (30 mL) and acetic acid (10 mL) was cooled to 0–5ꢀC
with ice-water bath. Into this stirred solution NaBH4 (0.25 g; 6.6 mmol)
was added in 8–10 portions during 1 h. The temperature of the mixture
was allowed to rt. After stirring for 1 h the reduction is complete (TLC,
eluent: hexane–EtOAc 1:1, treating with NH3 vapor; Rf 8<Rf 7). Then
the mixture was evaporated in vacuo, the residue dissolved in a mixture
of water (50 mL) and CH2Cl2 (50 mL). Whileshaking themixture, thepH
of the water phase was adjusted to 8–9 with ammonia. Water phase was
separated and extracted repeatedly with CH2Cl2 (2 ꢃ 25 mL). Thecom-
bined organic phase was dried (Na2SO4), treated with 2 N HCl/MeOH
(pH 2) and evaporated. MeOH/diethyl ether treatment of the residue
afforded colorless crystals of the dinitrile hydrochloride salt (8). Yield:
2.34 g (85%), m.p. 219–221ꢀC.
For the purpose of characterization aliquot salt was transformed into
crystallinebase. M.p. 59–61 ꢀC (hexane). Analysis: calculated C 75.28%,
H 7.16%, N 17.56%; found C 75.09%, H 7.10%, N 17.44%. IR (KBr):
2240 cmÀ1 (CN). 1H NMR (CDCl3): 1.61 (2H, m, 3- and 5-Hax),
1.84–2.10 (5H, m, 3- and 5-Heq þ 2- and 6-Hax þ 4-H), 2.97 (2H, m, 2-
and 6-Heq), 3.55 (1H, d, J ¼ 6.2 Hz, NC-CH-CN), 3.51 (2H, s, N-CH2-
Ph), 7.28–7.36 (5H, m, benzyl aromatic protons). 13C NMR (CDCl3):
28.65 (NC-CH-CN), 29.35 (C3 þ C5), 37.90 (C4), 52.30 (C2 þ C6),
62.63 (N-CH2-Ph), 111.63 (CN), 127.13 (C40), 128.23 (C30), 128.92
(C20), 137.82 (C10).
a-Cyano-(N-benzyl-piperidin-4-yl)-acetamide (11)
When the reaction leading to cyanoester 10 was repeated in dry
conditions (dry solvents, argon gas protection, acidification of the mix-
ture after formation of iminoether 9 with dry HCl gas), a mixtureof
cyanoamide 11 and cyanoester 10 was formed (in about 5:1 ratio).
From this mixture (TLC, eluent: CH2Cl2–MeOH 20:1; Rf 10 ꢂ Rf 11)
cyanoamide could be isolated easily by crystallization as follows.
The mixture was first evaporated in vacuo, the reminder dissolved in
water–methanol 4:1 and treated with ammonia (pH 8). The precipitate
was filtered, washed with water, and dried. Starting from 2.4 g (10 mmol)
unsaturated dinitrile 7 a crudemixture(2.0 g) was obtainde, the
recystallization of which in ethyl acetate gave pure cyanoamide 11
(1.35 g; 48%). M.p. 176–177ꢀC. Analysis: calculated C 70.01%, H 7.44%,

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4-Substituted N-Benzyl-piperidines
2335
N 16.33%; found C 69.88%, H 7.37%, N 16.21%. IR (KBr): 1680 (CO
amide), 2235 (CN), 3280 cmÀ1 (amideNH 2). 1H NMR (CDCl3 þ DMSO-
d6): 1.48 (2H, m, 3- and 5-Hax), 1.69 (1H, m, 4-H), 1.80–2.09 (4H, m, 3-
and 5-Heq þ 2- and 6-Hax), 2.88 (2H, m, 2- and 6-Heq), 3.43 (1H, d,
J ¼ 7.42 Hz, NC-CH-CONH2), 3.47 (2H, s, N-CH2-Ph), 7.10 þ 7.60
(1H þ 1H, 2 ꢃ brs, NH2), 7.28–7.36 (5H, m, benzyl aromatic protons).
13C NMR (CDCl3 þ DMSO-d6): 28.83 þ 28.95 (C3 þ C5), 35.73 (C4),
42.75 (NC-CH-CONH2), 51.71 þ 51.78 (C2 þ C6), 61.59 (N-CH2-Ph),
116.17 (CN), 125.69 (C40), 126.92 (C30), 127.67 (C20), 137.24 (C10),
165.49 (CO).
Disodium N-Benzyl-piperidin-4-yl-malonate (12)
An intensively stirred suspension of cyanoester hydrochloride 10
(30.88 g; 0.1 mol) in a mixtureof 40% NaOH (215 mL) and watre
(285 mL) was heated under a reflux condenser in an oil bath tempered
between 95 and 100ꢀC. The suspension turns to solution after a few
minutes; after 40–50 min crystal separation was observed. The progress
of the reaction could only be monitored by IR measurement: a small
sample was cooled, filtered, and dried. At the end of the reaction no
amideband (1660 cm À1) is detected. Usually 70–80 h heating is required.
Then the suspension was cooled, filtered, and washed with a small
amount of ice-cold water. After drying colorless crystals of disodium
salt 12 (31.1 g; 97%) was obtained. M.p. over 300ꢀC. Analysis: calculated
C 56.08%, H 5.33%, N 4.36%, Na 14.31%; found C 55.88%, H 5.19%,
N 4.25%, Na 14.52%. IR (KBr): 1575 and 1590 cmÀ1(CO2À).
Disodium salt 12 can be similarly prepared from crude cyanoamid 11
(yield: 85–90%).
Dimethyl N-Benzyl-piperidin
-4-yl-malonate Hydrochloride (13)
To the stirred suspension of disodium salt 12 (3.21 g; 10 mmol) in dry
methanol (50 mL) 7 N HCl/MeOH (5 mL) was admixed. The suspension
was stirred overnight at rt, then evaporated in vacuo. The reminder was
dissolved in water (50 mL), and the pH of the solution—cooled in ice-
water bath—was set to 8 by careful addition of ammonia. The suspension
was extracted with CH2Cl2 (3 ꢃ 20 mL), thecombined organic phasewas
dried (Na2SO4), treated with 2 N HCl/MeOH (pH 2) and evaporated.

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2336
Dornyei et al.
MeOH/diethyl ether treatment of the residue afforded colorless crystals
of thedimethyl malonatehydrochloridesalt (
13). Yield: 2.74 g (80%),
m.p. 187–188ꢀC. Analysis: calculated C 59.73%, H 7.08%, N 4.10%, Cl
10.37%; found C 59.68%, H 7.16%, N 4.03%, Cl 10.44%.
For spectroscopic investigation aliquot salt was transformed into oily
1
base. IR (KBr): 1730 and 1745 cmÀ1 (CO ester). H NMR (CDCl3): 1.39
(2H, m, 3- and 5-Hax), 1.65 (2H, m, 3- and 5-Heq), 1.99 (2H, m, 2- and 6-
Hax,), 2.13 (1H, m, 4-H), 2.87 (2H, m, 2- and 6-Heq), 3.20 (1H, d,
J ¼ 7.3 Hz, OC-CH-CO), 3.48 (2H, s, N-CH2-Ph), 3.71 (6H, s, OCH3),
7.25–7.35 (5H, m, benzyl aromatic protons). 13C NMR (CDCl3): 29.92
(C3 þ C5), 36.05 (C4), 52.25 þ 52.31 (OCH3), 53.20 (C2 þ C6), 57.26
(OC-CH-CO), 63.12 (N-CH2-Ph), 126.86 (C40), 128.07 (C30), 129.02
(C20), 138.29 (C10), 168.80 (CO).
Methyl N-Benzyl-piperidin-4-yl-acetate Hydrochloride (15)
The intensively stirred solution of disodium salt 12 (32.1 g; 0.1 mol) in
distilled water (100 mL) was cooled in ice-water bath and cc HCl
(100 mL) was added carefully and in many portions (strong foaming
dueto CO evolution!). The mixture was then heated under a reflux
2
condenser by the means of a 100ꢀC oil bath. Progress of the reaction
can befollowed by TLC (leuent: CH
2Cl2-MeOH 20:1, after treatment
with NH3 vapor; Rf 15<Rf 13). Sampling method: a small amount
(0.5–1 mL) of reaction mixture was evaporated to dryness and esterified
with 2 N HCl/MeOH. When the decarboxylation is complete (about
48 h), the solution was evaporated in vacuo to dryness. To the solid
residue MeOH (150 mL) and 7 N HCl/MeOH (15 mL) was admixed
and stirred at rt overnight, then evaporated in vacuo. The reminder
was dissolved in water (250 mL) and the pH of the solution—cooled in
ice-water bath—was set to 8 by careful addition of ammonia. The sus-
pension was extracted with CH2Cl2 (3 ꢃ 100 mL), thecombined organic
phasewas dride (Na 2SO4), treated with 2 N HCl/MeOH (pH 2) and
evaporated. Crystallization of the residue in MeOH/Et2O gavecolorless
crystals of the methyl acetate hydrochloride salt 15. Yield: 21.3 g (75%),
m.p. 183–185ꢀC. Analysis: calculated C 63.48%, H 7.81 %, N 4.94%, Cl
12.49%; found C 63.61%, H 7.70%, N 4.88%, Cl 12.34%. IR (KBr):
1725 (CO ester), 3440 cmÀ1(þNH).
For spectroscopic investigation aliquot salt was transformed into oily
base. IR (film): 1725 cmÀ1 (CO ester). 1H NMR (CDCl3): 1.33 (2H, m, 3-
and 5-Hax), 1.68 (2H, m, 3- and 5-Heq), 1.78 (1H, m, 4-H), 1.98 (2H, m, 2-
and 6-Hax), 2.23 (2H, d, J ¼ 7 Hz, CH2-CO), 2.86 (2H, m, 2- and 6-Heq),

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4-Substituted N-Benzyl-piperidines
2337
3.48 (2H, s, N-CH2-Ph), 3.65 (3H, s, OCH3), 7.25–7.35 (5H, m, benzyl
aromatic protons). 13C NMR (CDCl3): 31.98 (C3 þ C5), 32.82 (C4), 40.90
(CH2-CO), 51.27 (OCH3), 53.40 (C2 þ C6), 63.28 (N-CH2-Ph), 126.81
(C40), 128.04 (C30), 129.06 (C20), 138.37 (C10), 173.01 (CO).
N-Benzyl-piperidin-4-yl-acetic Acid Hydrochloride (14)
Methyl acetate hydrochloride 15 (1.42 g; 5 mmol) was dissolved and
refluxed in 2 N HCl (10 mL) for 6 h. Then the solution was evaporated in
vacuo to dryness. The residue (1.32 g) crystallized in MeOH/EtOAc gave
thehydrochloridesalt of acid 14 (1.15 g; 85%). M.p. 135ꢀC. Analysis:
calculated C 62.33%, H 7.47%, N 5.19%, Cl 13.14%; found C 62.19%,
H 7.29%, N 5.08%, Cl 13.30%. IR (KBr): 1705 (CO), 3400 cmÀ1 (þNH).
NMR data of the base are equivalent with those reported earlier.[5]
N-Benzyl-piperidine-4-ethanol (4)
Into the intensively stirred and argon gas protected suspension of
LiAlH4 (15.2 g; 0.4 mol) in dry THF (750 mL) the methyl acetate hydro-
chloridesalt 15 (28.4 g; 0.1 mol) was carefully added in many portions at
rt. Progress of the reduction can be followed by TLC (eluent: CHCl3–
MeOH 8:1, after treatment with NH3 vapor; Rf 4 ¼ 0.4, Rf 15 ¼ 0.8).
After 2 h the reduction is complete. The mixture was then cooled with
ice-water bath and the complex decomposed by careful addition of water
(15 mL), 15% NaOH (15 mL), and water (45 mL) again. The suspension
was stirred overnight at rt, then the precipitate, which turned from grey
to white, was filtered off and washed with THF (3 ꢃ 100 mL). Thecom-
bined THF phase was evaporated in vacuo, the oily reminder dissolved in
CHCl3 (150 mL) and washed with water (50 mL). The organic phase was
dried (Na2SO4) and evaporated again; vacuum distillation of the
reminder (22 g; quantitative yield) gave the ethanol 4 as colorless liquid
(19.7 g; 90%). B.p. 152–155ꢀC/1 Hgmm, n2D0 ¼ 1.5359. Analysis: calcu-
lated C 76.67%, H 9.65%, N 6.39%; found C 76.80%, H 9.61%, N
6.29%. IR (film): 3350 cmÀ1 (OH). 1H NMR (CDCl3): 1.30 (2H, m,
CH2CH2OH), 1.42–1.52 (3H, m, 3- and 5-Hax þ 4-H), 1.64 (2H, m, 3-
and 5-Heq), 1.94 (2H, m, 2- and 6-Hax), 2.20 (1H, brs, OH), 2.86 (2H, m,
2- and 6-Heq), 3.48 (2H, s, N-CH2-Ph), 3.63 (2H, t, CH2OH), 7.25–7.35
(5H, m, benzyl aromatic protons). 13C NMR (CDCl3): 32.18 (C3 þ C5),
32.22 (C4), 39.33 (CH2-CH2OH), 53.71 (C2 þ C6), 60.19 (CH2OH), 63.44

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Dornyei et al.
(N-CH2-Ph), 126.84 (C40), 128.03 (C30), 129.22 (C20), 138.20 (C10).
1H NMR data are equivalent with those reported by Dutta et al.[4]
ACKNOWLEDGMENTS
Theauthors wish to thank Ma rta Roczkov and Katalin Welker for
technical assistance. Financial support of this research in the framework
of 1/047 NKFP MediChem project is gratefully acknowledged.
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Received in the Netherlands October 15, 2002