The enantioselective synthesis of (S)-(+)-mianserin and (S)-(+)-epinastine

Article abstract of DOI:10.3762/bjoc.11.164

A simple enantioselective synthetic procedure for the preparation of mianserin and epinastine in optically pure form is described. The key step in the synthetic pathway is the asymmetric reduction of the cyclic imine using asymmetric transfer hydrogenation conditions.

Full text of DOI:10.3762/bjoc.11.164

The enantioselective synthesis of (S)-(+)-mianserin
and (S)-(+)-epinastine
Piotr Roszkowski*1, Jan. K. Maurin2,3 and Zbigniew Czarnocki1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 1509–1513.
1Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093,
Warsaw, Poland, 2National Medicines Institute, Chełmska 30/34,
00-725 Warsaw, Poland and and 3National Centre for Nuclear
Research, Andrzeja Sołtana 7, 05-400 Otwock-Świerk, Poland
doi:10.3762/bjoc.11.164
Received: 10 June 2015
Accepted: 18 August 2015
Published: 28 August 2015
Email:
Piotr Roszkowski* - roszkowski@chem.uw.edu.pl
Associate Editor: J. N. Johnston
* Corresponding author
© 2015 Roszkowski et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
chiral diamines; enantioselective reduction; epinastine; mianserin;
ruthenium complexes
Abstract
A simple enantioselective synthetic procedure for the preparation of mianserin and epinastine in optically pure form is described.
The key step in the synthetic pathway is the asymmetric reduction of the cyclic imine using asymmetric transfer hydrogenation
conditions.
Introduction
Mianserin (1) is a tetracyclic compound widely used as a drug manufacture of mianserin enantiomers both the above
in the treatment of depression. Despite the fact that the (S)-(+)- mentioned processes are rather unjustified economically and the
enantiomer of mianserin is more potent than the (R)-antipode in most advantageous method could be the enantioselective syn-
pharmacological tests for antidepresant activity [1-3], it is still thesis. Considering our experience in asymmetric synthesis of
administered as a racemate probably due to the fact that no structurally similar aptazepine [8], we applied this protocol to
serious adverse effects have been recorded for the (R)-enan- the preparation of (S)-mianserin. The key step in the proposed
tiomer. Interestingly, no enantioselective synthesis of mianserin synthetic pathway is the enantioselective reduction of an endo-
has been developed so far. The synthesis of racemic mianserin cyclic imine that led to the chiral amine. Interestingly, starting
was originally described by Organon [4,5], and in 1999 Jackson from this intermediate we obtained mianserin and also another
and Subasinghe presented a method for the separation of important active substance, epinastine, in enantiomerically pure
mianserin enantiomers with (+)- or (−)-di-p-toluoyltartaric acid form (Figure 1).
[6]. Later, the diastereoselective synthesis of (R)-mianserin
using (S)-(−)-α-methylbenzylamine as a chiral auxiliary was Epinastine (2) is a histamine H1 receptor antagonist and is used
described by the Czarnocki group [7]. For the commercial as racemic mixture in eye drops to relieve the symptoms of
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Beilstein J. Org. Chem. 2015, 11, 1509–1513.
When the cyclization was carried out in toluene or without the
solvent, only traces of the imine were detected. Alternatively
the condensation of N-chloroacetyl-2-benzylaniline and subse-
quent reaction with potassium phthalimide proposed by Moffett
[15] may be used for this step with comparable results. The
imine 6 was then transformed to the enantiomerically enriched
amine 7 with the aid of asymmetric transfer hydrogenation
(ATH) process [8,10,11].
Figure 1: The structure of mianserin 1 and epinastine 2.
allergic conjunctivitis. Analogously as in the case of mianserin, As in our synthesis of aptazepine [8], we initially used the chiral
the (S)-enantiomer is the more active form [9].
ruthenium complex 11 which contain (1R,2R)- or (1S,2S)-N-
tosyl-1,2-cyclohexanediamine as chiral ligand (Figure 2).
In a key step in the enantioselective synthesis of mianserin and
epinastine we applied the asymmetric reduction of the prochiral The reaction was carried out in acetonitrile using an azeotropic
imine by asymmetric hydrogen transfer reaction (ATH) [10-14]. mixture of formic acid/triethylamine as hydrogen source with
The proposed strategy could be used for the preparation of the 50:1 substrate to catalyst ratio. Under these conditions the
title compounds and their structural analogues.
desired amine was obtained in only 11% yield and with an
enantioselectivity of 60% ee (Table 1). The low chemical yield
probably results from the limited solubility of the imine in
Results and Discussion
The synthetic pathway is presented in Scheme 1. The reaction acetonitrile. When dichloromethane was used as a solvent, the
of 2-benzylaniline (3) with N-phthalylglycyl chloride (4) gave chemical yield increased to 65% and the stereoselectivity
amide 5 in 87% yield. The Bischler–Napieralski condensation achieved 92% ee (Table 1, entries 2 and 3). Additionally, chlo-
of amide 5 using phosphorus oxychloride in acetonitrile led to roform and dimethylformamide were tested as solvents. The
endocyclic imine 6 in 36% yield. The unreacted compound 5 reduction in chloroform gave worse results (45% yield and
could be fully recycled.
73% ee) than the reaction in dichloromethane, but the hydro-
Scheme 1: Enantioselective synthesis of (S)-(+)-mianserin.
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Applying dimethylformamide as a solvent led to lower asym-
metric induction and to significant reduction of the yield to
21%.
The recrystallization of amine 7 (60–95% ee) from a chloro-
form/methanol/diethyl ether mixture gave this compound with
46–91% recovery of the pure enantiomer. A single recrystalliza-
tion is sufficient for the amine enantioenriched above 75% but
in the case of the amine with a lower optical purity (60–75%) a
double recrystallization was applied. The values of specific
rotation were [α]D23 +68.1 (c 1, CHCl3) and [α]D23 −68.3 (c 1,
CHCl3), which could not be changed by repeated crystalliza-
tion steps. Confirmation of the optical purity of compound 7 by
HPLC (Daicel OD-H) could not be obtained because of its
insufficient solubility in a hexane/2-propanol mixture. The
absolute configuration of amine (S)-7 obtained by reduction of
Figure 2: Catalysts used in ATH.
genation of imine 6 in DMF using (R,R)-11 gave the product 6 using (R,R)-11 as catalyst was confirmed by X-ray analysis
with the highest enantiomeric excess 95%, but with only 26% (Figure 3).
chemical yield (Table 1, entry 6).
Subsequently, the synthetic procedure developed by us for
Subsequently other catalysts were tested in order to improve the aptazepine was applied [8]. Amide 8 was obtained in 94% yield
efficiency of the reduction. The catalyst 12, which is based on by reacting amine 7 and ethyl chloro(oxo)acetate in
N-tosyl-(1S,2S)-1,2-diphenylethane-1,2-diamine (TsDPEN), dichloromethane in the presence of triethylamine. The removing
gave amine 7 with 72–73% ee regardless of the solvent used, of the phthaloyl protecting group from 8 using hydrazine gave
with the exception of acetonitrile (Table 1, entries 8–10). In an intermediate with a free amino group which is cyclised in
CH3CN this catalyst is inactive and the product was not formed. situ to dioxopiperazine 9 in 90% yield. In the next step,
The solvent effect on the chemical yield was similar to that desmethylmianserin (10) was obtained in 81% yield by reduc-
observed with catalyst 11 (Table 1). Finally, the ruthenium tion of the carbonyl groups using a 1.0 M solution of lithium
complex 13 modified with amine developed by us [16] was aluminum hydride in THF. Finally, the reaction between deriva-
tested. This catalyst possesses similar activity to catalyst 12 and tive 10 and methyl iodide led to optical pure (S)-(+)-mianserin
gave the product with 75% enantiomeric excess and 52% yield. (1) (as confirmed by chiral HPLC) in 67% yield.
Table 1: The asymmetric reduction imine 6 by asymmetric transfer hydrogenationa.
Entry
Catalyst
Solvent
Time (h)
Yield (%)
[α]D23
ee (%)b, ()c
1
(R,R)-11
(R,R)-11
(S,S)-11
(R,R)-11
(S,S)-11
(R,R)-11
(S,S)-12
(S,S)-12
(S,S)-12
(S,S)-12
(R,R,R)-13
(R,R,R)-13
CH3CN
CH2Cl2
CH2Cl2
CHCl3
CHCl3
DMF
72
24
24
24
24
24
74
24
24
24
24
24
11
65
63
45
47
26
0
+41.0
+62.8
−62.2
+50.1
−49.3
+65.0
−
60 (S)
92 (S)
91 (R)
73 (S)
72 (R)
95 (S)
−
2
3
4
5
6
7
CH3CN
CH2Cl2
CHCl3
DMF
8
51
56
23
52
21
−49.0
−50.3
−50.1
+51.6
+42.1
72 (R)
73 (R)
73 (R)
75 (S)
62 (S)
9
10
11
12
CH2Cl2
DMF
aThe reaction was carried out at 22–24 °C using imine 6 (0.284 mmol) in solvent (5 mL) and a formic acid/triethylamine mixture (5:2, 1 mL) with a sub-
strate to catalyst ratio S/C = 50. bDetermined by the value of the specific rotation of the isolated product. cDetermined by the comparison with X-ray
data.
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Beilstein J. Org. Chem. 2015, 11, 1509–1513.
Supporting Information
Supporting Information File 1
Experimental procedures, spectroscopic and analytical data,
and copies of NMR spectra for all described compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-11-164-S1.pdf]
References
1. Pinder, R. M.; van Delft, A. M. L. Acta Psychiatr. Scand. 1983, 302,
59–71. doi:10.1111/j.1600-0447.1983.tb00359.x
2. Marshall, R. J. Br. J. Clin. Pharmacol. 1983, 15, 263S–268S.
doi:10.1111/j.1365-2125.1983.tb05874.x
3. Hand, T. H.; Marek, G. J.; Seiden, L. S. Psychopharmacology (Berlin)
1991, 105, 453–458. doi:10.1007/BF02244363
Figure 3: The ORTEP diagram for X-ray analysis of compound (S)-7.
4. van der Burg, W. J.; Gisors, J. D. Polycyclic piperazines. U.S. Patent
US3,534,041, Oct 13, 1970.
In order to obtain standards for HPLC analysis, racemic deriva-
tives 7–10 and 1 were made (Scheme 1). Compounds 7–9 were
insoluble in hexane/2-propanol mixture, a typical mobile phase
for HPLC analysis on an OD-H column. Therefore chromato-
graphic analysis was done for amines 10 and 1 only. For
mianserin satisfactory resolution conditions were found that
confirmed the optical purity of the final product (S)-1 [17].
5. van der Burg, W. J.; Bonta, I. L.; Delobelle, J.; Ramon, C.; Vargaftig, B.
J. Med. Chem. 1970, 13, 35–39. doi:10.1021/jm00295a010
6. Jackson, R. W.; Subasinghe, K. R. Resolution of optically-active
compounds. WO Patent WO99/16769, April 8, 1999.
7. Pawłowska, J.; Czarnocki, Z.; Wojtasiewicz, K.; Maurin, J. K.
Tetrahedron: Asymmetry 2003, 14, 3335–3342.
doi:10.1016/S0957-4166(03)00582-2
8. Roszkowski, P.; Maurin, J. K.; Czarnocki, Z. Synthesis 2012, 241–246.
doi:10.1055/s-0031-1289646
The preparation of optically pure amine 7 allows also for its
transformation to epinastine (2). The synthesis is presented in
Scheme 2 and is based on the modified procedure described by
Schneider [18]. The reaction of (S)-(+)-7 with hydrazine led to
derivative 13 with deprotected amine function. Subsequent con-
densation with cyanogen bromide gave (S)-(+)-epinastine (2) in
nearly quantitative yield.
9. ter Laak, A. M.; Venhorst, J.; Donné-Op den Kedler, G. M.;
Timmerman, H. J. Med. Chem. 1995, 38, 3351–3360.
doi:10.1021/jm00017a019
10.Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1996, 118, 4916–4917. doi:10.1021/ja960364k
11.Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97–102.
doi:10.1021/ar9502341
12.Roszkowski, P.; Maurin, J. K.; Czarnocki, Z. Tetrahedron: Asymmetry
2006, 17, 1415–1419. doi:10.1016/j.tetasy.2006.04.023
13.Roszkowski, P.; Czarnocki, Z. Mini-Rev. Org. Chem. 2007, 4, 190–200.
doi:10.2174/157019307781369959
Conclusion
In summary, we have presented a simple enantioselective syn-
thesis of (S)-(+)-mianserin and (S)-(+)-epinastine. Chirality was
introduced in a key step by asymmetric transfer hydrogenation.
This synthetic procedure could be used for the preparation of
other compounds variously substituted at the aryl rings.
14.Czarnocki, S. J.; Wojtasiewicz, K.; Jóźwiak, A. P.; Maurin, J. K.;
Czarnocki, Z.; Drabowicz, J. Tetrahedron 2008, 64, 3176–3182.
doi:10.1016/j.tet.2008.01.088
15.Moffett, R. B. J. Heterocycl. Chem. 1980, 17, 341–350.
doi:10.1002/jhet.5570170226
Scheme 2: Enantioselective synthesis of (S)-(+)-epinastine.
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Beilstein J. Org. Chem. 2015, 11, 1509–1513.
16.Roszkowski, P.; Maurin, J. K.; Czarnocki, Z. Tetrahedron: Asymmetry
2013, 24, 643–650. doi:10.1016/j.tetasy.2013.04.010
17.Cirilli, R.; Orlando, V.; Ferretti, R.; Turchetto, L.; Silvestri, R.;
De Martino, G.; La Torre, F. Chirality 2006, 18, 621–632.
doi:10.1002/chir.20298
18.Schneider, H. Verfahren zur Herstellung von
3-Amino-9,13b-dihydro-1H-dibenz[c,f]imidazol[1,5-a]azepin-hydrochlori
d. Eur. Pat. Appl. EP0496306 A1, Jan 18, 1992.
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