An improved and scalable process for 3,8-diazabicyclo[3.2.1]octane analogues

Article abstract of DOI:10.1016/j.cclet.2010.11.030

An improved and scalable process for substituted 3,8-diazabicyclo[3.2.1] octane was developed. N-Benzyl-2,5-dicarbethoxy-pyrrolidine 2 was reduced to N-benzyl-2,5-dihydroxymethylpyrrolidine 9 and subsequently debenzylated to afford N-Boc-2,5-dihydroxymeth

Full text of DOI:10.1016/j.cclet.2010.11.030

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Chinese Chemical Letters 22 (2011) 523–526
www.elsevier.com/locate/cclet
An improved and scalable process for 3,8-diazabicyclo[3.2.1]
octane analogues
*
Long Jiang Huang, Da Wei Teng
College of Chemical Engineering, Qingdao University of Science & Technology, Qingdao 266042, China
Received 23 August 2010
Available online 1 March 2011
Abstract
An improved and scalable process for substituted 3,8-diazabicyclo[3.2.1]octane was developed. N-Benzyl-2,5-dicarbethoxy-
pyrrolidine 2 was reduced to N-benzyl-2,5-dihydroxymethylpyrrolidine 9 and subsequently debenzylated to afford N-Boc-2,5-
dihydroxymethylpyrrolidine 10. After mesylation of the diol 10 and cyclization with benzylamine, a diversity of scaffold, 3,8-
diazabicyclo[3.2.1]octane analogue 12 was obtained in a total yield of 42% in five steps.
#
2010 Da Wei Teng. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 3,8-Diazabicyclo[3.2.1]octane; Scaffold; Process development
The piperazine nucleus is often found embedded in chemotherapic agents exhibiting a wide range of biological
activities [1,2]. As an analogue and alternative of piperizine in drug discovery, compounds based on 3,8-
diazabicyclo[3.2.1]octanyl ring system received great interest for their biological acativities such as anti-tumor
activity [3], antiarrhythmic activity [4], antinociceptive activity [5], analgetic activity [5,6], as m-opioid receptor [7],
neuronal nicotinic acetylcholine receptor [8] as well as novel amide CCR5 antagonist [9].
Cignarella et al. [10] first reported the synthesis of 3,8-diazabicyclo[3.2.1]octane derivatives. Several 3-substituted-
-methyl-3,8-diazabicyclo[3.2.1]octanes were synthesized starting from 2,5-dicarbethoxypyrrolidine, which was
8
converted into N-carbobenzoxy-2,5-pyrrolidine dicarboxylic acid anhydride in three steps. The latter reacted with
appropriate amines to give 3-substituted-8-carbobenzoxy-3,8-diazabicyclo[3.2.1]octanes-2,4-diones from which the
corresponding bicyclic bases were obtained by reduction with lithium aluminium hydride. The process suffers from
several disadvantages such as long steps, tedious and labrious isolation of intermediates and low overall yields. A more
efficient synthesis of 3-benzyl-3,8-diazabicyclo[3.2.1]octanes was subsequently reported soon and has being used
today (Scheme 1) [3,5,9,11]. The key intermediate, 2-benzylcarbamyl-5-carbethoxy pyrrolidine 4 was obtained in an
overall yield of 87% based on the recovery of starting materials by refluxing 3 with benzylamine in xylene. 4 was then
heated at 200–210 8C to afford intermediate 5 from which the 3-benzyl-3,8-diazabicyclo[3.2.1]octane was obtained by
reduction with lithium aluminiun hydride. The modified synthesis is much shorter and efficient than the original one.
But it still has some drawbacks. The intermediates need to be isolated in each step, which result in labrious work-up
and isolation. The cyclization of the key intermediate 4 was carried out at high temperature. The total yield is only 17%
*
Corresponding author.
E-mail address: dteng@qust.edu.cn (D.W. Teng).
1001-8417/$ – see front matter # 2010 Da Wei Teng. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.11.030

[()TD$FIG]
5
24
L.J. Huang, D.W. Teng / Chinese Chemical Letters 22 (2011) 523–526
O
Br
OEt
a
C H O C
CO C H
2
2
5
b
2
5
2
N
CO2C2H5
EtO
c
C H O C
2
5
2
N
Br
O
H
Bn
1
2
3
O
HN
d
e
NBn
C H O C
CONHCH2C6H5
2
5
2
N
H
N
N
Bn
H
O
4
5
6
Scheme 1. Cignarella’s synthesis of mono-substituted 3,8-diazabicyclo[3.2.1]octane. Reagents and conditions: (a) BnNH
Pd/C, ethanol; (c) benzylamine, xylene, reflux; (d) 210 8C; (e) LiAlH , ether, 0 8C–r.t.
2
2
, benzene, reflux; (b) H ,
4
(
23% based on the conversion) in five steps. In our course to synthesize this intermediate, an improved and scalable
process of diverse substituted 3,8-diazabicyclo [3.2.1]octane was developed. The synthetic route was illustrated as
Scheme 3.
1
. Results and discussion
In our effort to search for novel antitumor compounds in drug discovery, we need to synthesize this scaffold in
kilogram quantities. We tried to use the same procedures as described by Cignarella [11a,b]. After mono-amidation of
ethyl 2,5-pyrrolidine dicarboxylate 3, the isolation of unreacted starting materials and product was difficult and the
yield is unsatisfactory, the subsequent cyclization is also not worked well in our hand. After several attempts to the
cyclization of the second ring, we found (Scheme 2) that when ethyl 2,5-pyrrolidine dicarboxylate 3 was reduced and
mesylated, the dimesylate 8 could be cylizated smoothly by refluxing with primary amines. This process is much easer
and the yield is reasonable. But it still has some drawbacks: the diol 7 was water soluble and hard to isolate, which also
result in tedious work up. It is also necessary to isolate the intermediates 7 and 8. The 3-benzyl-3,8-
diazabicyclo[3.2.1]octane 6 needs to be distillated at high vacuum.
Inspired by this result, we examined the same strategy from 2 without debenzylation. The results are as well as
expected. The yield of reduction of 2 is much better than that of reduction of 3 by lithium aluminium hydride. The
reaction is easy to work up. Based on those results, we proposed a modified synthesis of the bicyclic ring system
(Scheme 3). In order to maximize the diversity of the scaffold, we synthesized the di-substituted 3,8-diazabicyclo
[()TD$FIG]
HN
a
HO
OH
b
MsO
OMs
c
C H O C
CO2C2H5
2
5
2
N
H
N
H
N
H
N
Bn
3
7
8
6
Scheme 2. alternative synthesis of mono-substituted 3,8-diazabicyclo[3.2.1]octane. Reagents and conditions: (a) LiAlH
Et N, r.t. CH Cl ; (c) BnNH , CH CN, reflux.
4
, ether, 0 8C–r.t.; (b) MsCl,
3
2
2
2
3
[()TD$FIG]
HO
OH
a
b
C H O C
CO2C2H5
2
5
2
N
N
Bn
Bn
2
9
Boc
HO
OH
c
MsO
OMs
d
N
N
N
Boc
Boc
N
Bn
1
0
11
12
Scheme 3. Synthesis of substituted 3,8-diazabicyclo[3.2.1]octane. Reagents and conditions: (a) LiAlH
MeOH, 40 8C; (c) MsCl, Et N, r.t. CH Cl ; (d) BnNH , CH CN, reflux.
4 2 2
, THF, 0 8C–r.t.; (b) H , Pd/C, Boc O,
3
2
2
2
3

L.J. Huang, D.W. Teng / Chinese Chemical Letters 22 (2011) 523–526
525
[3.2.1]octane 12, which could be either de-Boc to modify the amine in 3-position or debenzylated to modify the amine
in 8-position and/or both.
The 2,5-dicarbethoxypyrrolidine 2 was synthesized from meso-a,a-dibromoadipate 1 by modifying the Braun and
Seeman’s method [12]. In our hand, starting with one kilogram of ethyl meso-a,a-dibromoadipate 1, we obtained the
2
,5-dicarbethoxypyrrolidine 2 (888 g) quantitively by refluxing with equimolar benzylamine in toluene for 4 h
compared a yield of 82.5% in benzene for 24 h [12]. Reduction of 2 by lithium aluminium hydride in tetrahydrofuran
gives N-benzyl-2,5-dihydroxymethylpyrrolidine 9. Debenzylation of 9 in the mixture of di-tert-butyl dicarbonate and
methanol by hydrogenation using Pd/C catalyst afford N-Boc-2,5-dihydroxymethylpyrrolidine 10. Mesylation of the
diol 10 with methanesulfonyl chloride in dichloromethane, we obtained tert-butyl 2,5-bis(((methylsulfonyl)ox-
y)methyl)pyrrolidine-1-carboxylate 11. Refluxing 11 with benzylamine in acetonitrile afford the desired compound 3-
benzyl-8-Boc-3,8-diazabicyclo[3.2.1]octane 12. We also found by optimization that it is unnecessary to isolate the
intermediates in each step. After regular work up, the intermediates (2, 9, 10, and 11) were obtained and used in next
step. The 3-benzyl-8-Boc-3,8-diazabicyclo[3.2.1]octane 12 (370 g) was obtained by recrystallization in petroleum
ether [13–16]. The total yield is 42% in five steps.
2
. Conclusion
We developed an improved simple and scalable process for the synthesis of 3,8-diazabicyclo[3.2.1]octane
analogues, which can be used in the synthesis of diverse 3,8-diazabicyclo[3.2.1]octane derivatives.
Acknowledgment
This research was partially supported by the program of research fund for returning scholars of Ministry of
Education of China (No. 200812053).
References
[
[
1] J.W. Tracy, L.T. Webster, H.F. Chambers, et al., The Pharmacological Basis of Therapeutics, 10th ed., 2001, p. 1059.
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[
[
[
[
[
3] R. Filosa, A. Peduto, P. de Caprariis, et al. Eur. J. Med. Chem. 42 (2007) 293.
4] S. Villa, D. Barlocco, G. Cignarella, et al. Eur. J. Med. Chem. 36 (2001) 495.
5] D. Barlocco, G. Cignarella, D. Tondi, et al. J. Med. Chem. 41 (1998) 674.
6] G. Cignarella, E. Testa, J. Med. Chem. 11 (1968) 592.
7] (a) D. Barlocco, G. Cignarella, G. Giovanni, et al. J. Comput. Aided Mol. Des. 7 (1993) 557;
(
(
b) D. Barlocco, G. Cignarella, P. Vianello, et al. Farmaco 53 (1998) 557;
c) D. Barlocco, F. Paola, F. Walter, Farmaco 48 (1993) 387.
[
[
8] L. Toma, P. Quadrelli, W.H. Bunnelle, et al. J. Med. Chem. 45 (2002) 4011.
9] D.C. Pryde, M. Corless, D.R. Fenwick, et al. Bioorg. Med. Chem. Lett. 19 (2009) 1084.
[
[
10] (a) G. Cignarella, N. Gianciancomo, J. Org. Chem. 25 (1961) 1500;
b) G. Cignarella, N. Gianciancomo, E. Occelli, J. Org. Chem. 26 (1961) 2747.
11] (a) E. Occelli, L. Fontanella, A. Diena, et al. Farmaco, Edizione Scientifica 40 (1985) 86;
(
(
(
(
(
(
b) E. Occelli, L. Fontanella, A. Diena, et al. Farmaco, Edizione Scientifica 33 (1978) 401;
c) E. Occelli, L. Fontanella, A. Diena, et al. Farmaco, Edizione Scientifica 24 (1969) 418;
d) G. Cignarella, T. Emilio, J. Med. Chem. 11 (1968) 592;
e) S.C. Smith, P.D. Bentley, Tetrahedron Lett. 43 (2002) 899;
f) H. Liu, T.M. Cheng, H.M. Zhang, et al. Pharm. Med. Chem. 336 (2003) 510.
[
[
12] J. von Braun, J. Seeman, Ber 56 (1923) 1840.
1
13] Spectral data of compound 2: H NMR (500 MHz, CDCl
3
): d 7.32 (m, 2H), 7.27 (m, 2H), 7.23 (m, 1H), 4.05 (dd, 4H, J = 10.5 Hz, J = 7.5 Hz),
): d 173.4 (2C), 137.5, 129.5 (2C), 128.0 (2C), 127.2, 77.4 (2C),
13
3
.96 (s, 2H), 2.08 (m, 4H), 1.19 (t, 6H, J = 7.5 Hz); C NMR (125 MHz, CDCl
3
+
+
0.6, 57.8 (2C), 28.7 (2C), 14.1 (2C); LRMS: MS (ES ) m/z = 306.2 (M+1) .
6
1
3
[14] Spectral data of compound 6: H NMR (500 MHz, CDCl ): d 7.26 (m, 5H), 6.90 (br, 1H), 3.94 (s, 2H), 3.56 (s, 2H), 2.78 (d, 2H, J = 12.0 Hz),
1
3
2
5
.71 (d, 2H, J = 12.5 Hz), 2.13 (m, 2H), 2.06 (m, 2H); C NMR (125 MHz, CDCl ): d 138.6, 128.8 (2C), 128.4 (2C), 127.2, 65.0, 64.3 (2C),
3
+
8.8 (2C), 29.3 (2C); LRMS: MS (ES ) m/z = 203.1 (M+1) .
+
1
[15] Spectral data of compound 10: H NMR (500 MHz, CDCl
1
3
): d 3.94 (s, 2H), 3.82 (s, 4H), 3.51 (d, 2H, J = 7.5 Hz), 1.98 (m, 4H), 1.46 (s, 9H);
+
3
+
3
C NMR (125 MHz,CDCl ): d 156.5, 80.7, 65.5, 64.4, 60.6 (2C), 28.4 (3C), 26.9 (2C); LRMS: MS (ES ) m/z = 232.1 (M+1) .

526
L.J. Huang, D.W. Teng / Chinese Chemical Letters 22 (2011) 523–526
[
16] Typical procedure: To a suspension of LiAlH
900 mL) at 0 8C dropwise. The mixture was stirred for five minutes. Then water (200 mL) and a solution of 10% NaOH (200 mL) were added
dropwise at 0 8C. The mixture was filtered and the cake was washed with dichloromethane. The filtrate was combined and evaporated to obtain
(600 g, impure). It was dissolved in ethanol (3500 mL) and di-tert-butyl dicarbonate (600 g, 2.75 mol) and Pd/C (10 g) was added. The
4
(198 g, 5.21 mol) in THF (4000 mL), was added a solution of 2 (888 g, 2.912 mol) in THF
(
9
mixture was hydrogenated at 40 8C and 60 psi hydrogen pressure for four hours. The mixture was cooled and filtered. The filtrate was
evaporated to obtain 10 (630 g, impure). It was dissolved in dichloromethane (1000 mL) and triethylamine (700 g, 6.92 mol) was added, then
methanesulfonyl chloride (550 g, 4.80 mol) was added dropwise at 0 8C. The mixture was allowed to warm to room temperature and stirred
overnight. The mixture was washed sequentially with water, a solution of 10% citric acid and brine. The organic phase was dried over
anhydrous sodium sulfate and evaporated to obtain 11 (800 g, impure). It was dissolved in acetonitrile (1000 mL) and benzylamine (762 g,
7.12 mol) was added. The mixture was heated to reflux overnight. The mixture was evaporated and the residue was dissolved in ethyl acetate,
filtered through a silica pad, washed with water, a solution of 10% citric acid and brine. The organic phase was dried over anhydrous sodium
1
sulfate and evaporated. The compound 12 was obtained by recrystallization from petroleum ether as white solid (370 g, 42.1% in five steps). H
3
NMR (500 MHz, CDCl ): d 7.31 (m, 4H), 7.26 (m, 1H), 4.20 (s, 1H), 4.09 (s, 1H), 3.47 (s, 2H), 2.61 (d, 2H, J = 10.0 Hz), 2.31 (s, 1H), 2.24 (s,
1
3
1
5
3
H), 1.90 (s, 2H), 1.83 (s, 2H), 1.47 (s, 9H); C NMR (125 MHz, CDCl ): d 153.7, 138.9, 128.7 (2C), 128.2 (2C), 127.0, 79.2, 61.9, 58.2, 57.7,
+
+
4.7, 53.8, 28.5 (3C), 27.8; LRMS: MS (ES ) m/z = 303.2 (M+1) .