Optimized synthesis of new LE404-derived azecine-prodrugs

Article abstract of DOI:10.1016/j.tetlet.2017.08.007

Dibenzoazecines represent a class of high-affinity dopamine and serotonin receptor antagonists. The former synthesis of the lead structure 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-ol (LE404) has been 5 steps with a total yield of 13%. The present work enabled the synthesis of LE404 with a much higher yield. Based on this research, further azecin derivatives were synthesized with the aim to improve pharmacokinetic parameters.

Full text of DOI:10.1016/j.tetlet.2017.08.007

Tetrahedron Letters xxx (2017) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Optimized synthesis of new LE404-derived azecine-prodrugs
Stephanie Zergiebel a, Hans-Dieter Arndt b, Andreas Seeling a,
⇑
a Institute of Pharmacy, Friedrich-Schiller University Jena, Philosophenweg 14, 07743 Jena, Germany
b Institute of Organic Chemistry and Macromolecular Chemistry, Friedrich-Schiller University Jena, Humboldtstr. 10, 07743 Jena, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Dibenzoazecines represent a class of high-affinity dopamine and serotonin receptor antagonists. The for-
mer synthesis of the lead structure 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-ol (LE404) has
been 5 steps with a total yield of 13%. The present work enabled the synthesis of LE404 with a much
higher yield. Based on this research, further azecin derivatives were synthesized with the aim to improve
pharmacokinetic parameters.
Received 19 July 2017
Accepted 2 August 2017
Available online xxxx
Keywords:
Azecines
LE404
Ó 2017 Elsevier Ltd. All rights reserved.
Prodrugs
Neuroleptics
Introduction
Results and discussion
An imbalance of the neurotransmitters dopamine and serotonin
is strongly involved in the pathology of schizophrenia. Therefore,
the substance class of the benzindoloazecines merge the basic
structures of these two neurotransmitters in one molecule.1
In further research, the indole ring was substituted by a ben-
zene ring. The dibenzoazecines, obtained in this way, show a sim-
ilar affinity in receptor binding studies, compared with the
benzindoloazecines.2 In the in vivo tests, the substance LE404 (7)
was clearly superior to the other derivatives. LE404 is equally
potent as the tested standard substances haloperidol and risperi-
done.2 In addition to that, LE404 has a 5-fold higher therapeutic
range than the standard substances. Because the maximum
potency of LE404 in vivo is quickly reached after 30 min and the
effect thereafter falls strongly, the aim is to develop further deriva-
tives with a prolonged half-life.2 Three ester derivatives were
tested in vitro and in vivo. With the LE404-isobutanoic acid ester,
the duration of action has been increased to 120 min.3 The current
work reports an improved synthesis of LE404 and the synthetic
pathway to various derivatives of LE404, which could have a longer
efficacy in vivo. The synthesis of LE404 was reported in 5 steps with
an overall yield of 13%.4 In order to obtain LE404 in sufficient quan-
tity the synthesis was optimized for further derivatizations. The
derivatization was focused on various esters and carbamates.
Moreover, a propinyl-group has been introduced in various places
in the molecule which may inhibit liver metabolism.5
Scheme 1 illustrates the optimized synthetic pathway leading
to LE404. The synthesis is started from commercially available
3-methoxyphenylethylamine 1 and isochromanone 2 to obtain
the benzamide 3 in 74% yield. The reaction is catalyzed by
potassium cyanide. A Bischler-Napieralski-cyclisation procedure
receives the quinolizine 4. Treatment with methyl iodide afforded
the N-methylated compound 5 in 43% yield over 2 steps. The ether
bond was cleaved with boron tribromide to give phenol 6 in
93% yield. Finally, a Birch reduction yields LE404 by benzylic
fragmentation (quantitative conversion). The overall yield was
improved to 30%.
The previous work reported a yield of 13% over all 5 steps.4 By
adding KCN as a catalyst, the yield of the ester aminolysis in the
first step (a) was improved from 60% to 74% (Scheme 1). In the sec-
ond step (b), the starting material was dissolved in acetonitrile and
POCl3 was added dropwise under ice cooling. Due to the higher
dilution of components and lowering the reaction temperature
compared to earlier procedures,4 the selectivity of the reaction
could be improved and thus the yield could be increased. Further-
more, if the crude product was reacted with methyl iodide directly
(step c) it resulted in a higher yield than when amine 4 was first
purified, because the recrystallization of 5 proceeded effectively,
whereas the purification of amine 4 resulted in loss of material.
In the next step (d), the methyl ether was cleaved with boron tri-
bromide instead of 47% hydrogen bromide solution, increasing
the yield by 9%. In the last step (e), Birch reduction of ammonium
salt 6 was carried out in liquid ammonia at À78 °C instead of
À40 °C, and for extraction chloroform instead of diethyl ether
⇑
Corresponding author.
E-mail address: b8sean@rz.uni-jena.de (A. Seeling).
http://dx.doi.org/10.1016/j.tetlet.2017.08.007
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Zergiebel S., et al. Tetrahedron Lett. (2017), http://dx.doi.org/10.1016/j.tetlet.2017.08.007

2
S. Zergiebel et al. / Tetrahedron Letters xxx (2017) xxx–xxx
Scheme 1. Reagents and conditions: a) KCN, 70 °C, 7 d; b) phosphoryl chloride, MeCN, 0 °C to rt, reflux 24 h; c) methyl iodide, MeCN, reflux, 48 h; d) boron tribromide,
chloroform, 0 °C to rt, 24 h; e) Na0, liq. ammonia, -78 °C to rt, 12 h.
was used, followed by silica gel filtration. The yield could such be
improved from 72%4 to nearly 100%.
Treatment of 7 with various carbamoyl chlorides gave the car-
bamates 18, 19 and 20 (Scheme 3). The yield ranged between
73% and 98%, depending on the carbamoyl chloride used. After
24 h the conversion was quantitative (monitored by TLC). More-
over, Scheme 3 shows three further derivatives. Reaction of 7 with
ethyl chloroformate afforded 21 in 87% yield as a colorless solid
after silica column purification. To obtain the toluene-4-sulfonic
acid ester, 7 was deprotonated with sodium hydride and was then
treated with toluene-4-sulfonic acid chloride. The used solvent was
a mixture of THF and DCM, to accommodate the different solubil-
ities of substrates and reagents. The optimal final mixing ratio of
THF/DCM was 3:1 and afforded sulfonate 22 in 97% yield. The reac-
tion conditions for the synthesis of the propargyl ether derivative
23 could be greatly simplified compared to the literature7 by using
sodium hydride for deprotonation and a solvent mixture of
toluene/DMF (1:1). The transformation was found to be complete
in 1 h. In addition, it was possible to carry out the reaction at room
temperature without refluxing, with a final yield of 99%.
The obtained lead structure 7 was first converted into ten differ-
ent esters (Scheme 2). Esterification of 7 afforded 8, 9 and 10,
respectively, in 85% yield using the appropriate acid chloride (step
a: benzoyl chloride, step b: p-methylbenzoyl chloride, step c: p-
methoxybenzoyl chloride) and sodium hydride to deprotonate
the phenol as previously described for 15, 16 and 17.3 The com-
pounds 11 and 12 were also prepared from the acid chlorides,
but in this case the acid chlorides were obtained from the car-
boxylic acids and not purchased commercially. The yield over
two steps is 71% for 11 and 77% for 12. The synthesis was carried
out over two steps without purification of the acid chloride
because this is very sensitive to hydrolysis and the yield is signifi-
cantly higher when the crude product is directly converted. To
obtain the amino acid esters 13 and 14, first a Steglich esterifica-
tion was carried out with the Boc-protected amino acids6 (yield:
74% for N-(tert-butoxycarbonyl)-L-valine-ester, yield: 54% for N-
(tert-butoxycarbonyl)- -leucine-ester). In the next step, the protec-
L
In order to derivatize the nitrogen in the 10-membered azecine
ring, access to the secondary amine was necessary. The synthetic
pathway is shown in Scheme 4. Step a and b afforded carbamate
25 in 91% yield, which was synthesized according to a literature
tive group was cleaved by hydrochloric acid in dioxane, and the
chloride salts of the azecines were obtained simultaneously. The
yield for 13 and 14 was 95%, respectively.
9
method.8 Following the work of Enzensperger et al. succeeded
in cleaving simultaneously the urethane and the methyl ether with
boron tribromide to form the secondary amine 27, albeit under
drastic conditions (reflux for 24 h, 10 equivalents boron tribro-
mide). Under controlled conditions, it was possible to cleave the
methyl ether selectively (step c) in 85% yield (? 26). By using a
sterically hindered base (N,N-diisopropylethylamine), the nitrogen
alkylation was successful without a protective group on the
phenol. Hence, amine 27 was directly converted with propargyl
bromide to amine 28 (yield: 96%).
Scheme 2. Reagents and conditions: a) benzoyl chloride, NaH, DCM, 0 °C to rt,
30 min; b) p-methylbenzoyl chloride, NaH, DCM, 0 °C to rt, 30 min; c) p-methoxy-
benzoyl chloride, NaH, DCM, 0 °C to rt, 30 min; d) acetyl chloride, NaH, DCM, 0 °C to
rt, 30 min3; e) isobutyryl chloride, NaH, DCM, 0 °C to rt, 30 min3; f) pivaloyl
chloride, NaH, DCM, 0 °C to rt, 30 min3; g) cyclopentanecarboxylic acid, oxalyl
chloride, DMF, DCM, 0 °C to rt, 60 min; h) 7, TEA, 0 °C to rt, 24 h; i) cyclohex-
anecarboxylic acid, oxalyl chloride, DMF, DCM, 0 °C to rt, 60 min; j) 7, TEA, 0 °C to rt,
Scheme 3. Reagents and conditions: a) 4-morpholine-carbonylchloride, NaH, DCM,
0 °C to rt, 24 h; b) dimethylcarbamoyl chloride, NaH, DCM, 0 °C to rt, 24 h; c) 1-
pyrrolidinecarbonyl chloride, NaH, DCM, 0 °C to rt, 24 h; d) ethyl chloroformate,
NaH, DCM, 0 °C to rt, 3 h; e) toluene-4-sulfonic acid chloride, NaH, THF/DCM (3:1),
0 °C to rt, 2 h; f) propargyl bromide, NaH, toluene/DMF (1:1), 0 °C to rt, 1 h.
24 h; k) N-(tert-butoxycarbonyl)-L-valine, DCC, DMAP, DMF, rt, 24 h; l) HCl in
dioxane, MeCN, 0 °C to rt, 2 h; m) N-(tert-butoxycarbonyl)-
DMF, rt, 24 h; n) HCl in dioxane, MeCN, 0 °C to rt, 2 h.
L-leucine, DCC, DMAP,
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S. Zergiebel et al. / Tetrahedron Letters xxx (2017) xxx–xxx
3
Experimental
Experimental procedures, characteristics and analytical data
(1H NMR, 13C NMR, IR, HRMS, elemental analysis, mp) of the com-
pounds can be found in the Supplementary data file.
Acknowledgement
The authors would like to thank Dr. Christoph Enzensperger for
the constructive scientific discussion.
Supplementary data
Supplementary data (experimental procedures, analytical data,
materials, equipment parameters) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/j.tet-
let.2017.08.007.
Scheme 4. Reagents and conditions: a) ethyl chloroformate, THF, À78 °C (4 h) to rt
(12 h);8 b) sodium cyanoborohydride THF, À78 °C (4 h) to rt (12 h);8 c) boron
tribromide, chloroform, rt, 24 h; d) boron tribromide, chloroform, reflux, 24 h; e)
propargyl bromide, N,N-diisopropylethylamine, DCM, 0 °C to rt, 12 h.
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Please cite this article in press as: Zergiebel S., et al. Tetrahedron Lett. (2017), http://dx.doi.org/10.1016/j.tetlet.2017.08.007