Stereoselective synthesis of (R)-(-)-mianserin

Article abstract of DOI:10.1016/S0957-4166(03)00582-2

(14bR)-2-Methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine, (R)-(-)-mianserin 1a was synthesised in several steps in good enantiomeric purity with the use of (S)-(-)-α-methylbenzylamine 5. The absolute configuration was assigned on the bas

Full text of DOI:10.1016/S0957-4166(03)00582-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3335–3342
Stereoselective synthesis of (R)-(−)-mianserin
J. Pawłowska,a Z. Czarnocki,a,* K. Wojtasiewicza and J. K. Maurinb,c
aFaculty of Chemistry, Warsaw University, Pasteura 1, 02-093, Warsaw, Poland
bDrug Institute, Chełmska 30/34, 00-750 Warsaw, Poland
cInstitute of Atomic Energy, 05-400 Otwock-Swierk, Poland
Received 7 July 2003; accepted 18 July 2003
Abstract—(14bR)-2-Methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f ]pyrazino[1,2-a]azepine, (R)-(−)-mianserin 1a was synthesised in
several steps in good enantiomeric purity with the use of (S)-(−)-a-methylbenzylamine 5. The absolute configuration was assigned
on the basis of X-ray data.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
The separation of the mianserin 1 enantiomers has been
achieved analytically by a GC method9 and on a larger
scale, with the use of chiral preparative HPLC.10 The
absolute configuration of (S)-(+)-mianserin was estab-
lished by X-ray crystallography of its hydrobromide.11
Only the synthesis of the racemic form of mianserin 1
has been reported.4 The synthesis of enantiopure chiral
compounds represents an important challenge in
organic chemistry since numerous classes of compounds
undergo ‘biodiscrimination’ within organisms12 and
reveal biological activity that strongly depends on their
stereostructures.
Mianserin 1 (Tolvon®, (14bRS)-2-methyl-1,2,3,4,10,
14b-hexahydrodibenzo[c,f ]pyrazino[1,2-a]azepine) the
tetracyclic compound of the piperazine-dibenzepine
group, is a drug for the treatment of depressive illness
and depression associated with anxiety.1 Its antidepres-
sant effect is mainly attributed to presynaptic a2-
adrenoreceptor blocking activity and to serotonin
receptors antagonism.2,3 This antidepressant has very
little, if any, activity on monoamine re-uptake mecha-
nisms.4 Based on its undefined mechanism of action,
mianserin 1 has been classified as an atypical antide-
pressant (Fig. 1).5
Stereoselective syntheses of compounds having pharma-
cological importance should preferably start from inex-
pensive and readily available chiral inductors,
preferably accessible in both enantiomeric forms. In
this context we decided to use (S)-(−)-a-methylbenzyl-
amine 5 as a chiral auxiliary in the synthesis of non-
racemic mianserin 1 because it is known to be effective,
reasonably priced and easy to remove by reductive
methods.13,14 Also, in our group amine 5, as well as its
enantiomer have been successfully applied for the syn-
thesis of isoquinoline alkaloids15 and lortalamine
derivatives.16
Mianserin 1 is administered as a racemate, although the
(S)-(+)-enantiomer was more potent than (R)-(−)-con-
gener in pharmacological tests for antidepressant
activity.6–8
2. Results and discussion
Figure 1.
In the presented stereoselective synthesis of mianserin 1,
we started with 6-chloromethylmorphanthridine 44 as a
precursor for the introduction of chirality adjuvant.
* Corresponding author. E-mail: czarnoz@chem.uw.edu.pl
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00582-2

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J. Pawłowska et al. / Tetrahedron: Asymmetry 14 (2003) 3335–3342
Scheme 1.
Scheme 2.
Scheme 3.
This compound was prepared by the reaction of 2-ben-
zylaniline 2 with chloroacetyl chloride in the presence
of pyridine to obtain 2-benzylchloroacetanilide 3 in
79% yield (Scheme 1). Bischler–Napieralski condensa-
tion of 2-benzylchloroacetanilide 3 with POCl3 in aceto-
nitrile gave 6-chloromethylmorphanthridine 4 in 86%.
The prochiral imine moiety in compound 6 was there-
fore subjected to a series of reductions under different
conditions that gave the mixtures of diastereomeric:
N - [(6R) - 6,11 - dihydro - 5H - dibenzo[b,e]azepin - 6-
ylmethyl]-N-[(1%S)-1-phenylethyl]amine 9a and N-[(6S)-
6,11 - dihydro - 5H - dibenzo[b,e]azepin - 6 - ylmethyl] - N-
[(1%S)-1-phenylethyl]amine 9b. When sodium borohy-
dride in methanol was used as the reducing agent,
almost no stereoselection was observed regardless the
temperature. The result is not surprising since the
stereoselection is based on 1,4-chirality transfer. Com-
parable results were obtained in the case of lithium
aluminium hydride in THF but the yield was consider-
ably lower. Catalytic hydrogenation (Adams’, EtOH/
HCl) was also non-selective.
Chloroimine 4 was subsequently treated with (S)-(−)-a-
methylbenzylamine 5 to afford crude compound 6 in
approximately 70% yield (Scheme 2). Amidine deriva-
tive 6 proved to be very unstable and we were unable to
collect all the required spectroscopic data of sufficient
quality. However, compound 6 underwent the subse-
quent steps with reasonable yields. First, we planned to
take advantage on the chemistry of acylimmonium ions
and compound 6 was subjected to the reaction with
oxalyl chloride with the hope of forming cyclic enamide
7, the more rigid structure of which would possibly
allow higher stereoselectivity within the reduction.
Unfortunately, compound 7 proved to be extremely
unstable and the only product that was obtained in this
reaction was 8, probably as the result of decomposition
of 7 and the influence of the solvents. On the other
hand, attempts to reduce compound 7 without any
purification procedure gave rise to intractable mixtures
(Scheme 3).
However, when sodium borohydride is treated with a
controlled amount of carboxylic acid, a modified reduc-
ing agent forms that is weaker, more sterically demand-
ing and therefore more selective.17 Indeed, when imine
6 was treated with sodium diacetoxy-, triacetoxy- and
tri-i-butyroylborohydrides an increasing diastereoselec-
tivity, up to 76:24, was observed alas with lowering of
the yield (Scheme 4). Attempts to improve the selectiv-
ity by temperature or solvent variations were unsuccess-
ful. Selected results are given in Table 1.

J. Pawłowska et al. / Tetrahedron: Asymmetry 14 (2003) 3335–3342
3337
Scheme 4.
Table 1.
The diastereomeric composition after the reduction step
was established on the basis of H NMR spectra taken
1
Reduction conditions
Yield
(%)
Diastereomers 9a
and 9b
on crude reaction mixtures. Both isomers 9a and 9b
showed very similar chromatographic properties and
their effective separation required repeated and very
careful column chromatography. Moreover, slow
decomposition of compounds 9a and 9b could be
observed. Fortunately, when 9a or 9b were treated with
oxalyl chloride in the presence of pyridine, stable dike-
topiperazine derivatives 10a and 10b were formed,
respectively. Also, both diastereomers 10a and 10b
showed better separation properties than in the case of
9a and 9b. Consequently, we found that the mixture
after the reduction could be more efficiently purified
and separated after its conversion to the mixture of
appropriate diamides (14bR)-2-[(1%S)-1-phenylethyl]-
1,2,10,14b - tetrahydrodibenzo[c,f ]pyrazino[1,2 - a]-
azepine-3,4-dione 10a and (14bS)-2-[(1%S)-1-phenyl-
ethyl]-1,2,10,14b-tetrahydrodibenzo[c,f ]pyrazino[1,2-a]-
azepine-3,4-dione 10b (Scheme 5).
1) NaBH4/MeOH/rt
2) NaBH4/MeOH/−70°C
3) Na(CH3COO)2BH2/MeOH/rt
4) Na(CH3COO)3BH/MeOH/rt
5) Na(i-C3H7COO)3BH/MeOH/rt
68
64
67
57
48
48:52
57:42
63:37
73:27
76:24
It may be mentioned here that 9b was the first com-
pound to be eluted during the column chromatography,
whereas in case of amides 10a and 10b the order of the
elution was reversed. In the case of diketopiperazine
10b we were able to obtain a single crystal suitable for
an X-ray study that allowed the assignment of (14bS)
configuration at the heterocyclic part of the molecule
(Fig. 2).
Attempted reduction of compounds 10a or 10b with
lithium aluminium hydride led to the cleavage of CꢀN
bond and extensive decomposition, whereas with
borane–dimethyl sulfide complex (BMS)18 the reduction
of carbonyl groups proceeded smoothly to give prod-
ucts 11a or 11b in excellent yields (Schemes 6 and 7).
Scheme 5.
Final non-racemic (R)-(−)-mianserin 1a was obtained
from 11a in a two step reaction sequence in 58% overall
yield. The chiral auxiliary was removed by the
hydrogenolysis over palladium-on-carbon and the sec-
ondary amine thus formed was subsequently N-methyl-
ated using formaldehyde-sodium borohydride method
to obtain (R)-(−)-1a in over 92% enantiomeric excess
purity. The (S)-(+)-1a enantiomer could not be detected
upon analysis on the chiral GC column.
3. Experimental
The NMR spectra were recorded on a Varian Unity
Plus spectrometer operating at 500 and 200 MHz for
1H NMR and at 125 and 50 MHz for 13C NMR.
Tetramethylsilane (TMS) or solvents were used as inter-
nal standards. Chemical shifts were reported in ppm.

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J. Pawłowska et al. / Tetrahedron: Asymmetry 14 (2003) 3335–3342
Figure 2. X-Ray diffraction structure (ORTEP diagram) of diketopiperazine 10b.
Scheme 6.
Scheme 7.

J. Pawłowska et al. / Tetrahedron: Asymmetry 14 (2003) 3335–3342
3339
Mass spectra were collected on AMD 604 apparatus;
high-resolution mass spectra were acquiring using
LSIMS (positive ion mode), GC/MS was done at HP
6890 with a mass detector HP 5973 (oven 280°C,
injection 300°C, detector 300°C). ChiraDex b-Dex® 120
30 m/0.25 mm Supelco column was used for analytical
enantiomer separations. Optical rotation was measured
on a Perkin–Elmer 247 MC polarimeter. TLC analyses
were performed on Merck 60 silica gel glass plates and
visualised using iodine vapour. Column chromatogra-
phy was carried out at atmospheric pressure using
Silica Gel 60 (230–400 or under 400 mesh, Merck) or
on aluminium oxide (III Brockmann, Merck).
MgSO4. Column chromatography (silica gel, chloro-
form/ethanol, 9:1) afforded compound 8 in a yield of
1
1.63 g (78%). [h]2D2 −75 (c 1.2, CHCl3); H NMR (500
MHz, CDCl3), l (ppm): 7.34–7.28 (m, 5H, 5Harom.),
5.15 (q, 1H, J=7.0 Hz, CH), 4.34 (q, 2H, J=14.5 Hz,
CH2), 1.61 (br.s, 1H, NH), 1.57 (d, 3H, J=6.5 Hz,
CH3), 1.38 (t, 3H, J=7.0 Hz, CH3); 13C NMR (125
MHz), CDCl3, l (ppm): 160.8, 155.6, 141.7, 128.8,
127.8, 126.2, 63.2, 49.4, 21.2, 14.0.
Reductions with sodium borohydride: A solution of 5.35
g (16.4 mmol) of imine 6 in 250 mL of methanol was
treated while stirring with 4.5 g (0.12 mol) of NaBH4,
which was added in five portions. After 24 h, the
solvent was evaporated in vacuo, the residue was
treated with 50 mL of 10% HCl and then made basic
with Na2CO3aq, extracted with CHCl3 and dried over
MgSO4. Short-path column chromatography (alu-
minium oxide III, 98:2 cyclohexane/ethyl acetate)
afforded 3.7 g (68%) yield of the mixture of N-[(6R)-
6,11 - dihydro - 5H - dibenzo[b,e]azepin - 6 - ylmethyl]-N-
[(1%S)-1-phenylethyl]amine 9a and N-[(6S)-6,11-
dihydro-5H-dibenzo[b,e]azepin-6-ylmethyl]-N-[(1%S)-1-
phenylethyl]amine 9b in the ratio 48:52 as calculated
from the integration of the signals at 1.41 and 1.45 ppm
Preparation of 2-benzylchloroacetanilide 3: According to
van der Burg procedure,4 we used a mixture of 25 g
(0.14 mol) 2-benzylaniline 2, 15 mL of pyridine in 125
mL of benzene and 11.9 g (0.11 mol) of chloroacetyl
chloride in 20 mL benzene to obtain 28 g (79%) of
compound 3 as yellow crystals. Mp 117–119°C, mp4
119–120°C.
Preparation of 6-chloromethylmorphanthridine 4: To a
suspension of 7.5 g (0.30 mol) 2-benzylochloroac-
etanilide 3 in 120 mL of acetonitrile a sample of 38 g
(0.25 mol) POCl3 was added in one portion. The reac-
tion mixture was stirred and refluxed for 1.5 h. The
volatile components were then evaporated in vacuo, the
residue was washed with NaHCO3aq, extracted with
CHCl3 and dried over MgSO4. Column chromatogra-
phy (silica gel, chloroform) afforded 6.0 g (86%) of
compound 4 as yellow crystals. Mp 139–142°C, mp4
138–139°C; 1H NMR (200 MHz, CDCl3) l (ppm):
7.56–7.16 (m, 8H, H-1, H-2, H-3, H-4, H-7, H-8, H-9,
H-10), 4.79 (br.s, 2H, 2H-6a), 3.63 (s, 2H, 2H-11); 13C
NMR (50 MHz, CDCl3) l (ppm): 164.5, 144.4, 143.4,
132.6, 131.5, 130.4, 127.1, 127.1, 126.9, 126.5, 125.3,
48.9, 38.8; GC/MS m/z (%): 102 (19), 165 (37), 178
(19), 192(100), 206 (37), 241 (80) M+.
1
in H NMR. Two diastereomeric forms were separated
by means of a very careful column chromatography
(silica gel, 99:1 chloroform/methanol). Analytical data
1
for compound 9a: [h]2D2 −89 (c 1.2, CHCl3); H NMR
(500 MHz, CDCl3) l (ppm): 7.36–7.33 and 7.28–7.25
(m, 5H, H-3%, H-4%, H-5%, H-6%, H-7%), 7.20–7.14 and
7.01–6.96 (m, 6H, H-1, H-3, H-7, H-8, H-9, H-10), 6.65
(td, 1H, J1=7.5 Hz, J2=1.0 Hz, H-2), 6.56 (br. d, 1H,
J=8.0 Hz, H-4), 4.96 (dd, 1H, J1=10.0 Hz, J2=4.0 Hz,
H-6), 4.55 and 3.71 (qAB, 2H, J=15.0 Hz, 2H-11), 3.91
(q, 1H, J=14.0 Hz, H-1%), 3.07 (dd, 1H, J1=11.5 Hz,
J2=4.0 Hz, H-6a), 2.90 (td, 1H, J1=11.5 Hz, J2=1.5
Hz, H-6a), 1.65 (br.s, 1H), 1.41 (d, 3H, J=7.0 Hz,
CH3); 13C NMR (125 MHz, CDCl3) l (ppm): 145.9,
139.7, 138.1, 129.9, 128.6, 128.4, 127.6, 127.4, 127.2,
126.8, 126.6, 124.9, 118.7, 118.2, 58.0, 54.9, 51.0, 30.2,
26.9.
Preparation of N-(11H-dibenzo[b,e]azepin-6-ylmethyl)-
N-[(1%S)-1-phenylethyl]amine 6: The mixture of 3.23 g
(13.4 mmol) 6-chloromethylmorphanthridine 4 and 4.05
g (33.5 mmol) (S)-(−)-a-methylbenzylamine 5 was
stirred at 50°C under argon. After 20 min the reaction
mixture was cooled and white crystals of amine hydro-
chloride were filtered off. The residue consisted of
compound 6 as very unstable oil, which could not be
effectively purified nor characterised and therefore it
had to be used without any further treatment. EI (70
eV) (%): 326 (45), 105(100); LSIMS HR (+) m/z (%):
105 (100), 327[M+H]+(60), 349[M+Na]+(20).
Analytical data for compound 9b: [h]2D2 +40.5 (c 1.2,
1
CHCl3): H NMR (500 MHz, CDCl3) l (ppm): 7.36–
7.31 and 7.26–7.24 (m, 5H, H-3%, H-4%, H-5%, H-6%,
H-7%), 7.19–7.13 and 7.01–6.96 (m, 6H, H-1, H-3, H-7,
H-8, H-9, H-10), 6.66 (td, 1H, J1=7.5 Hz, J2=1.0 Hz,
H-2), 6.59 (br.d, 1H, J=8.0 Hz, H-4), 4.74 (t, 1H,
J=5.5 Hz, H-6), 4.49 (br.s, 1H), 4.41 and 3.76 (qAB
,
2H, J=15.5 Hz, 2H-11), 3.86 (q, 1H, J=13.0 Hz, H-1%),
3.00 (br.d, 1H, J=2.0 Hz, H-6a), 2.99 (br.s, 1H, H-6a),
1.60 (br.s, 1H), 1.45 (d, 3H, J=7.0 Hz, CH3); 13C
NMR (125 MHz, CDCl3), l (ppm): 145.9, 139.6, 138.1,
129.9, 128.6, 128.5, 127.5, 127.4, 127.2, 126.8, 126.5,
125.6, 125.3, 118.9, 118.4, 58.9, 55.7, 52.1, 30.2, 26.9.
GC/MS m/z (%): 105(33), 134(15), 165(15), 179(2),
194(100), 328(2) M+.
Preparation of ethyl oxo{[(1S)-1-phenylethyl]amino}-
acetate 8: To a solution of 3.30 g (10.1 mmol) of the
crude imine 6, 2.1 mL (22.0 mmol) of triethylamine in
70 mL of dry THF cooled to −78°C and stirred mag-
netically under argon, the solution of 1.41 g (9.0 mmol)
of oxalyl chloride in 30 mL dry THF was added
dropwise. After 24 h of subsequent stirring white crys-
tals were filtered off, washed with CH2Cl2 and the
filtrate concentrated in vacuo. The residue was poured
into NaHCO3aq, extracted with CH2Cl2 and dried over
Alternatively, a suspension of 0.40 g (11.9 mmol) of
NaBH4 in 5 mL of methanol was introduced slowly
into a solution of 0.50 g (1.5 mmol) of imine 6 in
methanol cooled to −78°C and stirred. After 5 h the

3340
J. Pawłowska et al. / Tetrahedron: Asymmetry 14 (2003) 3335–3342
cooling bath was removed and the mixture was stirred
overnight. The solvent was evaporated in vacuo, the
J=14.5 Hz, H-1%), 4.89 (dd, 1H, J1=11.0 Hz, J2=3.5
Hz, H-14b), 4.50 and 3.42 (qAB, 2H, J=13.5 Hz, 2H-
10), 3.78 (td, 1H, J1=13.5 Hz, J2=2.5 Hz, H-1), 3.10
(dd, 1H, J1=13.5 Hz, J2=3.0 Hz, H-1), 1.52 (d, 3H,
J=7.5 Hz, CH3); 13C NMR (125 MHz), CDCl3, l
(ppm): 157.8, 157.0, 140.4, 139.2, 139.1, 136.2, 132.7,
129.3, 128,9, 128.7, 128.7, 128.4, 128.3, 128.2, 127.7,
127.6, 127.4, 127.3, 61.0, 51.4, 46.4, 38.3, 15.1; GC/MS
m/z (%): 105 (85), 132 (23), 165 (40), 178 (23), 193
(100), 249 (25), 339 (25), 382 (100) M+.
residue was washed with 10% HCl and Na2CO3aq
,
extracted with CHCl3 and dried (MgSO4). Column
chromatography (aluminium oxide III, 98:2 ethyl cyclo-
hexane/acetate) afforded 0.32 g (64%) of mixture of
compounds 9a and 9b in the ratio 57:42.
General procedure for the reductions of imine 6 with
modified borohydrides: The modified borohydride solu-
tion was obtained from NaBH4 in dry THF and the
calculated amount of the carboxylic acid.17
Analytical data for compound 10b: [h]2D2 +85 (c 1.2,
1
CHCl3); mp 143–150°C; H NMR (500 MHz, CDCl3),
l (ppm): 7.36–7.25 and 7.32–7.26 (m, 5H, H-3%, H-4%,
H-5%, H-6%, H-7%), 7.24–7.23 and 7.20–7.11 (m, 6H, H-7,
H-9, H-11, H-12, H-13, H-14), 7.04 (td, 1H, J1=8.0
Hz, J2=2.0 Hz, H-8), 6.83 (d, 1H, J=7.5 Hz, H-6),
6.01 (q, J=14.0 Hz, 1H, H-1%), 5.11 (dd, 1H, J1=10.5
Hz, J2=3.5 Hz, H-14b), 4.41 and 3.40 (qAB, 2H, J1=
14.0 Hz, 2H-10), 3.46 (td, 1H, J1=10.5 Hz, J2=3.5 Hz,
H-1), 3.30 (dd, 1H, J1=13.0 Hz, J2=4.0 Hz, H-1), 1.71
(d, 3H, J=7.0 Hz, CH3); 13C NMR (125 MHz, CDCl3)
l (ppm): 157.8, 156.9, 140.1, 139.1, 137.8, 136.6, 132.8,
129.5, 128.8, 128.6, 128.5, 128.4, 128.3, 128.1, 127.7,
127.7, 127.5, 127.4, 60.9, 51.3, 46.1, 38.4, 15.7.
In the case of Na(CH3COO)2BH2, a sample of 1.36 g
(22.8 mmol) of glacial acetic acid was added over a
period 20 min to a suspension 0.43 g (11.4 mmol)
NaBH4 in 25 mL of dry THF and the resulted mixture
was then stirred for 0.5 h. After that time, 0.26 g (6.8
mmol) of imine 6 was introduced and the contents of
the flash was stirred for 24 h. The mixture was then
poured onto 25 mL of 25% aqueous NaOH, stirred for
0.5 h, and extracted with ether. The combined extracts
were dried over Na2SO4 and concentrated in vacuo to
leave colourless oil. Column chromatography (alu-
minium oxide III, 98:2 cyclohexane/ethyl acetate)
afforded 0.18 g (67%) mixture of compounds 9a and 9b
in the ratio 63:37.
X-Ray intensity data for 10b were measured at T=293
K on a Kuma KM4 k-axis diffractometer using MoKa
,
radiation (u=0.71073 A). The structure was solved
In the case of other acyl borohydrides: Na(CH3-
COO)3BH and Na(i-C3H7COO)3BH, respective
amounts of 34.1 mmol of glacial acetic acid and 28.6
mmol of i-butyric acid were added and the procedure
that followed was the same as above. The stereochemi-
cal outcome was given in Table 1.
using direct methods from SHELXS-97 program19 and
refined by application of SHELXL-97 software.20
Crystal data for 10b: C25H22N2O2, M=382.45, mono-
clinic space group P21; a=8.7300(17), b=11.359(2),
3
,
,
c=10.270(2) A, i=91.26(3)°, V=1018.2(4) A , Z=2
and Dx=1.247 Mg/m3. Clear colourless columnar crys-
tal, v(MoKa)=0.080 mm−1, 3236 reflections measured,
3062 independent (Rint=0.0252), 1221 observed [I>
2|(I)]. The least squares on F2 (all reflections), R=
0.0534, wR=0.1708 (all). The crystal structure has been
deposited at the Cambridge Crystallographic Data Cen-
tre and allocated with the deposition number CCDC
212929. Apart from crystal structure reported here we
obtained also the structure of its solvate in which 10b
crystallised in the orthorhombic space group P21212
Preparation of (14bR)-2-[(1%S)-1-phenylethyl]-1,2,10,
14b-tetrahydrodibenzo[c,f]
pyrazino[1,2-a]azepine-3,4-
dione 10a and (14bS)-2-[(1%R)-1-phenylethyl]-1,2,10,14b-
tetrahydro dibenzo[c,f]pyrazino[1,2-a]azepine-3,4-dione
10b: A solution of 0.24 mL (3.0 mmol) of oxalyl
chloride in 2 mL of dry CH2Cl2 was introduced slowly
into a magnetically stirred solution of the mixture of
0.66 g (2.0 mmol) of amines 9a and 9b in 15 mL
CH2Cl2 with 0.38 mL (4.4 mmol) of pyridine at −78°C
under argon atmosphere. After 24 h, the white crystals
were filtered out and washed with CH2Cl2 and the
filtrate was concentrated in vacuo. The residue was
poured onto a suspension of NaHCO3, extracted with
CH2Cl2, dried over MgSO4 and concentrated. Two 20
mL portions of xylene were added and then removed in
vacuo and the residue was quenched with ethyl acetate,
affording the first crop of 30 mg of 10b in the form of
white crystals. Column chromatography of the mother
liquor (silica gel, cyclohexane/ethyl acetate, 85:15)
allowed the complete separation of the diastereomers in
70 mg (92%) chemical yield.
,
with a=12.241(7), b=18.053(7), c=10.459(6) A and
h=i=k=90°. The asymmetric part of the unit cell was
composed of one molecule of 10b and one disordered
ethanol molecule. These crystals were however of much
worse quality with the R of 0.081 for observed
reflections.
Preparation
of
(14bR)-2-[(1%S)-1-phenylethyl]-1,2,
3,4,10,14b-hexahydrodibenzo[c,f] pyrazino[1,2-a]azepine
11a: A sample of 30 mg (0.4 mmol) of borane dimethyl
sulphide complex (BMS) was introduced slowly into a
magnetically stirred solution of the solution of 0.30 g
(0.8 mmol) of diastereomer 10a in 10 mL of dry THF.
The mixture was then heated at reflux while dimethyl
sulfide distilled off. After 4 h, the product was
hydrolysed with 12% HCl and heated for 2 h. After
cooling, the product was neutralised with 20% NaOH
to pH 11, extracted with CH2Cl2 and dried over
Analytical data for compound 10a: [h]2D2 −156 (c 1.2,
1
CHCl3); mp 228–232°C; H NMR (500 MHz, CDCl3),
l (ppm): 7.47–7.35 (m, 5H, H-3%, H-4%, H-5%, H-6%,
H-7%), 7.27–7.24 and 7.18–7.11 (m, 6H, H-7, H-9, H-11,
H-12, H-13, H-14), 7.05 (td, 1H, J1=7.5 Hz, J2=1.5
Hz, H-8), 6.54 (d, 1H, J=7.5 Hz, H-6), 6.01 (q, 1H,

J. Pawłowska et al. / Tetrahedron: Asymmetry 14 (2003) 3335–3342
3341
MgSO4. Column chromatography (silica gel, chloro-
form) afforded colourless oil 0.26 g (94%) of compound
11a.Analytical data for compound 11a: [h]2D2 −341.8 (c
dried over MgSO4 and evaporated to leave the residue
that after column chromatography (silica gel, chloro-
form) afforded final (R)-(−)-mianserin 1a as a white
powder (25 mg, 58% yield). [h]2D2 −421 (c 1, C2H5OH);
1
1.1, CHCl3); H NMR (500 MHz, CDCl3), l (ppm):
1
7.35–7.30 and 7.25 and 7.22 (m, 5H, H-3%, H-4%, H-5%,
H-6%, H-7%), 7.17–7.12 and 7.09–7.07 and 7.02–6.96 (m,
6H, H-7, H-9, H-11, H-12, H-13, H-14), 6.96 (br d,
J=7.0 Hz, 1H, H-6), 6.84 (td, J1=7.5 Hz, J2=1.0 Hz,
1H, H-8), 4.79 and 3.27 (qAB, 2H, J1=12.5 Hz, 2H-10),
4.11 (br d, 1H, J=9.0 Hz, H-14b), 3.44 (q, 1H, J=13.0
Hz, H-1%), 3.15-3.10 (m, 2H, H-1, H-4), 2.86 (dd, 1H,
J1=11.0 Hz, J2=1.5 Hz, H-1), 2.44 (t, 1H, J=11.0 Hz,
H-4), 2.22 (td, 2H, J1=11.0 Hz, J2=2.5 Hz, 2H-3), 1.41
(d, 3H, J=6.5 Hz, CH3); 13C NMR (125 MHz, CDCl3)
l (ppm): 148.7, 143.6, 139.7, 139.4, 137.9, 129.6, 128.2,
128.1, 127.6, 127.1, 126.9, 126.8, 126.4, 122.1, 118.9,
66.8, 64.8, 60.3, 51.3, 51.1, 38.8, 19.9.
mp 114–119°C; H NMR (500 MHz, CDCl3), l (ppm):
7.18–6.99 (m, H-6, H-7, H-9, H-11, H-12, H-13, H-14),
6.87 (td, 1H, J1=7.5 Hz, J2=1.0 Hz, H-8), 4.82 and
3.30 (qAB, 2H, J=13.0 Hz, 2H-10), 4.08 (dd, 1H,
J1=10.5 Hz, J2=2.5 Hz, H-14b), 3.37 (td, 1H, J1=12.0
Hz, J2=3.0 Hz, H-1), 3.27–3.24 (m, 1H, H-4), 2.97 (dd,
1H, J1=11.5 Hz, J2=2.0 Hz, H-1), 2.88 (dt, 1H, J1=
11.0 Hz, J2=2.0 Hz, H-4), 2.42 (t, 1H, J=10.5 Hz,
H-3), 2.36 (s, 3H, CH3), 2.33 (dd, 1H, J1=11.0 Hz,
J2=3.5 Hz, H-3). Lit.21 [h]2D2 for compound (R)-(−)-1a
−457.6 (C2H5OH).
Compound 11b was obtained from diastereoisomer 10b
in a similar procedure.
Acknowledgements
Analytical data for compound 11b: [h]2D2 +157.7 (c 0.91,
We thank Mr. Dariusz Błachut from the Department of
Criminalistics, Internal Security Agency for acquiring
MS spectra. We also thank Institute of Nuclear Chem-
istry and Technology for making their X-ray equipment
available for us.
1
CHCl3); H NMR (500 MHz, CDCl3), l (ppm): 7.35–
7.30 and 7.25 and 7.22 (m, 5H, H-3%, H-4%, H-5%, H-6%
H-7%), 7.17–7.12 and 7.09–7.07 and 7.02–6.96 (m, 6H,
H-7, H-9, H-11, H-12, H-13, H-14), 6.85 (td, 1H,
J1=7.5 Hz, J2=1.0 Hz, H-8), 6.81 (dd, 1H, J1=8.5 Hz,
J2=2.0 Hz, H-6), 4.77 and 3.26 (qAB, 2H, J=12.5 Hz,
2H-10), 4.01 (dd, 1H, J1=10.0 Hz, J2=1.5 Hz, H-14b),
3.51 (q, 1H, J1=14.0 Hz, H-1%), 3.38 (td, 1H, J1=12.0
Hz, J2=3.0 Hz, H-1), 3.29-3.24 (m, 1H, H-4), 3.13 (dd,
1H, J1=11.5 Hz, J2=2.0 Hz, H-1), 2.81 (dt, 1H, J1=
11.5 Hz, J2=2.0 Hz, H-4), 2.38 (td, 2H, J1=11.0 Hz,
J2=3.0 Hz, 2H-3), 1.42 (d, J=7.0 Hz, 3H, CH3); 13C
NMR (125 MHz, CDCl3) l (ppm): 148.7, 143.5, 139.7,
139.3, 137.7, 129.5, 128.2, 127.9, 127.6, 127.1, 126.9,
126.7, 126.4, 126.4, 122.1, 118.9, 66.8, 64.4, 60.5, 51.4,
50.2, 38.8, 19.2; GC/MS m/z (%): 105 (20), 165 (10),
179 (15), 193 (35), 249 (100), 354 (31) M+.
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