PAPER
Enantioselective Synthesis of Aptazepine
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ed, and the mixture was basified with solid Na2CO3. The layers
were separated and the aqueous layer was extracted with CHCl3 (50
mL). The combined organic layers was washed successively with
2% aq HCl (15 mL) and distilled H2O (15 mL), dried (MgSO4), and
concentrated in vacuo. The residual oil was purified by column
chromatography (silica gel, CHCl3) to give colorless crystals; yield:
0.90 g (quant); mp 171–172 °C; [a]D23 –199 (c 1, CHCl3).
J = 13.0 Hz, 1 H, methylene bridge), 5.89 (dd, J1 = 2.0 Hz, J2 = 3.5
Hz, 1 H, pyrrole), 5.97 (dd, J1 = 2.5 Hz, J2 = 3.5 Hz, 1 H, pyrrole),
6.57 (dd, J1 = 2.0 Hz, J2 = 2.5 Hz, 1 H, pyrrole), 6.88–6.92 (m, 1 H,
Ar), 7.04–7.06 (m, 1 H, Ar), 7.13–7.16 (m, 1 H, Ar), 7.23–7.27 (m,
1 H, Ar).
13C NMR (125 MHz, CDCl3): d = 46.6, 50.8, 52.9, 56.2, 63.7, 107.1,
108.1, 119.7, 120.4, 122.4, 127.3, 129.3, 129.8, 134.6, 150.6.
1H NMR (500 MHz, CDCl3): d = 0.92 (t, J = 7.0 Hz, 3 H, CH3),
3.89 (q, J = 7.0 Hz, 2 H), 4.03–4.05 (m, 2 H), 4.65 (d, J = 13.5 Hz,
1 H, methylene bridge), 5.42 (d, J = 13.5 Hz, 1 H, methylene
bridge), 6.08–6.10 (m, 1 H, methine), 6.27–6.28 (m, 1 H, pyrrole),
6.52–6.54 (m, 1 H, pyrrole), 6.66–6.67 (m, 1 H, pyrrole), 7.36–7.38
(m, 2 H, Ar), 7.41–7.45 (m, 1 H, Ar), 7.73–7.76 (m, 2 H, Phth),
7.82–7.84 (m, 1 H, Ar), 7.90–7.93 (m, 2 H, Phth).
13C NMR (125 MHz, CDCl3): d = 13.5, 41.4, 50.6, 52.3, 61.7, 107.6,
110.1, 122.5, 123.4, 124.7, 128.2, 129.4, 129.8, 130.8, 132.1, 134.1,
135.9, 138.1, 161.6, 162.5, 168.4.
HRMS (ESI): m/z [M + H]+ calcd for C15H18N3: 240.1501; found:
240.1521.
(14bS)-1,3,4,14b-Tetrahydro-2H,10H-pyrazino[1,2-a]pyrro-
lo[2,1-c][1,4]benzodiazepine [(S)-11]
The enantiomer (S)-11 was similarly prepared as a solidifying oil;
[a]D23 –318 (c 0.5, CHCl3). The enantiomeric purity was determined
by HPLC [Chiracel OD-H, hexane–i-PrOH–Et2N (88:12:0.1), 1
mL/min]; the S-isomer eluted at 15.5 min.
(14bR)-2-Methyl-1,3,4,14b-tetrahydro-2H,10H-pyrazino[1,2-
a]pyrrolo[2,1-c][1,4]benzodiazepine [(R)-2; (+)-Aptazepine];
Typical Procedure
HRMS (ESI): m/z [M + Na]+ calcd for C25H21N3O5Na: 466.1379;
found: 466.1397.
Solid K2CO3 (29 mg, 0.21 mmol) and a soln of MeI (13.0 L, 0.21
mmol) in CHCl3 (0.2 mL) were added successively to a stirred soln
of tetracycle 11 (50 mg, 0.21 mmol) in anhyd CHCl3 (5 mL). The
suspension was refluxed for 2 h, cooled to r.t., and CHCl3 (20 mL)
and H2O (10 mL) were added. The layers were separated and the
aqueous layer was extracted with CHCl3 (2 × 15 mL). The organic
layer was dried (MgSO4) and concentrated to give a brown oil that
was purified by column chromatography (alumina, 0–1% MeOH–
CHCl3) to give a solidifying oil; yield: 39 mg (73%); [a]D23 +462 (c
0.5, CHCl3). The enantiomeric purity was determined by HPLC
analysis [Chiracel OD-H, hexane–i-PrOH–Et2N (90:10:0.1), 1 mL/
min]; the R-isomer eluted at 11.9 min.
1H NMR (500 MHz, CDCl3): d = 2.27–2.32 (m, 1 H), 2.35 (s, 3 H,
N-CH3), 2.38–2.42 (m, 1 H), 2.92–2.96 (m, 2 H), 3.26 (dt, J1 = 2.5
Hz, J2 = 11.5 Hz, 1 H), 3.36–3.41 (m, 1 H), 4.25 (dd, J1 = 2.5 Hz,
J2 = 10.5 Hz, 1 H, methine), 4.51 (d, J = 13.0 Hz, 1 H, methylene
bridge), 5.48 (d, J = 13.0 Hz, 1 H, methylene bridge), 5.91 (dd,
J1 = 2.0 Hz, J2 = 3.5 Hz, 1 H, pyrrole), 5.97 (dd, J1 = 2.5 Hz,
J2 = 3.5 Hz, 1 H, pyrrole), 6.57 (dd, J1 = 2.0 Hz, J2 = 2.5 Hz, 1 H,
pyrrole), 6.89–6.92 (m, 1 H, Ar), 7.06–7.08 (m, 1 H, Ar), 7.13–7.15
(m, 1 H, Ar), 7.23–7.27 (m, 1 H, Ar).
Ethyl [(11S)-11-(N-Phthalimidomethyl)-5H-pyrrolo[2,1-
c][1,4]benzodiazepine-10(11H)-yl](oxo)acetate [(11SR)-9] (9)
The enantiomer (S)-9 was similarly prepared as colorless crystals;
[a]D23 +204 (c 1, CHCl3); mp 171–172 °C.
(14bR)-1,14b-Dihydro-2H,10H-pyrazino[1,2-a]pyrrolo[2,1-
c][1,4]benzodiazepine-3,4-dione [(R)-10]; Typical Procedure
A mixture of ester 9 (0.5 g, 1.13 mmol) and N2H4 (0.21 mL, 6.77
mmol) in 99.8% EtOH (15 mL) was refluxed for 2 h. After evapo-
ration of volatile components, the residue was purified by column
chromatography (silica gel, 0–1.5% MeOH–CHCl3) to give a light-
beige solid: yield: 274 mg (90%); mp 320 °C (dec); [a]D23 +152.8 [c
0.25, CH2Cl2–MeOH (3:1)].
1H NMR (500 MHz, CDCl3): d = 3.59 (dt, J1 = 3.5 Hz, J2 = 13.5
Hz, 1 H), 3.87–3.92 (m, 1 H), 5.02 (d, J = 14.5 Hz, 1 H, methylene
bridge), 5.21 (d, J = 14.5 Hz, 1 H, methylene bridge), 5.31–5.33 (m,
1 H, methine), 5.89 (dd, J1 = 2.5 Hz, J2 = 3.5 Hz, 1 H, pyrrole), 6.05
(dd, J1 = 2.0 Hz, J2 = 3.5 Hz, 1 H, pyrrole), 6.85 (dd, J1 = 2.0 Hz,
J2 = 2.5 Hz, 1 H, pyrrole), 7.26–7.29 (m, 1 H, Ar), 7.35–7.40 (m, 2
H, Ar), 7.44–7.60 (m, 1 H, Ar), 8.87 (s, 1 H, NH).
13C NMR (125 MHz, CDCl3): d = 43.8, 49.1, 55.9, 106.8, 108.7,
123.3, 126.4, 127.5, 128.3, 128.5, 128.8, 134.9, 138.9, 157.1, 157.6.
HRMS (ESI): m/z [M + Na]+ calcd for C15H13N3O2Na: 290.0905;
found: 290.0908.
13C NMR (125 MHz, CDCl3): d = 45.9, 50.8, 51.3, 55.5, 61.8, 65.1,
107.1, 108.2, 119.8, 120.4, 122.5, 127.3, 129.3, 129.7, 134.5, 150.2.
HRMS (ESI): m/z [M + Na]+ calcd for C16H19N3Na: 276.1477;
found: 276.1469.
(14bS)-1,14b-Dihydro-2H,10H-pyrazino[1,2-a]pyrrolo[2,1-
c][1,4]benzodiazepine-3,4-dione [(S)-10]
(14bR)-2-Methyl-1,3,4,14b-tetrahydro-2H,10H-pyrazino[1,2-
a]pyrrolo[2,1-c][1,4]benzodiazepine [(S)-2; (–)-Aptazepine]
The enantiomer (S)-2 was similarly prepared as a solidifying oil;
[a]D23 –448 (c 0.5, CHCl3).
The enantiomer (S)-10 was similarly prepared as a light-beige solid;
mp 320 °C (dec); [a]D23 –152 [c 0.25, CH2Cl2–MeOH (3:1)].
(14bR)-1,3,4,14b-Tetrahydro-2H,10H-pyrazino[1,2-a]pyrro-
lo[2,1-c][1,4]benzodiazepine [(R)-11]; Typical Procedure
A 1.0 M soln of LiAlH4 in THF (1.0 mL) was added to a stirred sus-
pension of dione 10 (50 mg, 0.19 mmol) in anhyd Et2O (5 mL) and
the mixture was refluxed for 1 h then cooled to r.t. Et2O (50 mL) and
H2O (0.3 mL) were added, the precipitate was filtered off, and the
organic layer was dried (MgSO4) and concentrated. The residual oil
was purified by column chromatography (alumina, 0–2% MeOH–
CHCl3) to give a solidifying oil; 40 mg (88%); [a]D23 +313 (c 0.5,
CHCl3). The enantiomeric purity was determined by HPLC
[Chiracel OD-H, hexane–i-PrOH–Et2N (88:12:0.1), 1 mL/min]; the
R-isomer eluted at 16.9 min.
The enantiomeric purity was determined by HPLC analysis
[Chiracel OD-H, hexane–i-PrOH–Et2N (90:10:0.1), 1 mL/min]; the
S-isomer eluted at 8.5 min.
Acknowledgment
We acknowledge financial support from the Polish Ministry of Sci-
ence and Higher Education in the form of grant N N204 2117939.
References
(1) Hirschfeld, R. M.; Keller, M. B.; Panico, S.; Arons, B. S.;
Barlow, D.; Davidoff, F.; Endicott, J.; Froom, J.; Goldstein,
M.; Gorman, J. M.; Marek, R. G.; Maurer, T. A.; Meyer, R.;
1H NMR (500 MHz, CDCl3): d = 1.83 (s, 1 H, NH), 2.97–3.12 (m,
4 H), 3.21–3.27 (m, 2 H), 4.10 (dd, J1 = 5.5 Hz, J2 = 9.5 Hz, 1 H,
methine), 4.51 (d, J = 13.0 Hz, 1 H, methylene bridge), 5.51 (d,
© Thieme Stuttgart · New York
Synthesis 2012, 44, 241–246