Economical synthesis of tert-butyl (S)-3-aminopyrrolidine-1-carboxylate from L-aspartic acid

Article abstract of DOI:10.1080/00397911.2018.1509093

3-Aminopyrrolidine building block was used as the intermediate for many pharmaceutically active substances. Starting from L-aspartic acid, optically active (S)-tert-butyl-3-aminopyrrolidine-1-carboxylate was synthesized, and the reaction conditions were optimized in each step. The procedure of each step was discussed in detail and could be useful for the industrial preparation. This process was featured by readily available starting material, mild reaction conditions, easy work-up, and economy.

Full text of DOI:10.1080/00397911.2018.1509093

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Economical synthesis of tert-butyl (S)-3-
aminopyrrolidine-1-carboxylate from L-aspartic
acid
Zhi-Jian Han, Yang-Bing Li, Bao-Hong Gu, Yu-Min Li & Hao Chen
To cite this article: Zhi-Jian Han, Yang-Bing Li, Bao-Hong Gu, Yu-Min Li & Hao Chen (2018)
Economical synthesis of tert-butyl (S)-3-aminopyrrolidine-1-carboxylate from L-aspartic acid,
Synthetic Communications, 48:18, 2452-2456, DOI: 10.1080/00397911.2018.1509093
To link to this article: https://doi.org/10.1080/00397911.2018.1509093
View supplementary material
Published online: 08 Oct 2018.
Submit your article to this journal
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

V
R
SYNTHETIC COMMUNICATIONS
018, VOL. 48, NO. 18, 2452–2456
2
https://doi.org/10.1080/00397911.2018.1509093
Economical synthesis of tert-butyl (S)-3-aminopyrrolidine-1-
carboxylate from L-aspartic acid
a
a
b
b
a,b
Zhi-Jian Han , Yang-Bing Li , Bao-Hong Gu , Yu-Min Li , and Hao Chen
a
The Key Laboratory of the Digestive System Tumors of Gansu Province, Lanzhou University Second
b
Hospital, Lanzhou, China; Department of General Surgery, Lanzhou University Second Hospital,
Lanzhou, China
ABSTRACT
ARTICLE HISTORY
3-Aminopyrrolidine building block was used as the intermediate for
Received 1 February 2018
many pharmaceutically active substances. Starting from L-aspartic
acid, optically active (S)-tert-butyl-3-aminopyrrolidine-1-carboxylate
was synthesized, and the reaction conditions were optimized in each
step. The procedure of each step was discussed in detail and could
be useful for the industrial preparation. This process was featured by
readily available starting material, mild reaction conditions, easy
work-up, and economy.
KEYWORDS
Aminopyrrolidine deriva-
tives; aspartic acid; phase
transfer catalyst
GRAPHICAL ABSTRACT
Introduction
3-Aminopyrrolidine and its derivatives are important fine chemical intermediates, which
are widely used in the synthesis of pesticides and quinolones or cephalosporin pharma-
[1–4]
ceuticals, such as Ceftobiprole, Tosufloxacin, Tomopenem, or Clinafloxacin (Figure 1).
Many researches focused on exploring 3-aminopyrrolidine as a potential scaffold in discov-
[5]
ery of novel chronic myeloid leukemia inhibitors and chemokine receptor 2 antago-
[6,7]
nists.
These biological important fascinated numerous groups to explore efficient and
economic procedures to prepare optically active 3-aminopyrrolidines, and a number of
works on synthesizing 3-aminopyrrolidine have been disclosed to date starting from
CONTACT Hao Chen
Yumin Li liym@lzu.edu.cn
chenhao3996913@163.com
Lanzhou University Second Hospital, Lanzhou 730030, China;
Lanzhou University Second Hospital, Lanzhou 730030, China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the the publisher’s website.
ß 2018 Taylor & Francis Group, LLC

V
R
SYNTHETIC COMMUNICATIONS
2453
Figure 1. Antibacterial agents of 3-aminopyrrolidine as an essential component.
[
8–12]
naturally occurred aspartic acid.
synthesis strategy was also used for optically pure-aminopyrrolidines.
procedures provide good methods to prepare 3-aminopyrrolidines, the practice and econ-
Alternatively, resolution of a racemate or asymmetric
[13–15]
Although these
[16–20]
omy of them is still scarce to industrially synthesize 3-aminopyrrolidines.
Therefore,
there is still a need to discover a practical method to synthesize 3-aminopyrrolidine eco-
nomically. In this article, we report the details of the efficient synthesis of optically pure
compound 3-aminopyrrolidine 1 from L-Asp in a practical and economic protocol.
Results and discussion
(S)-tert-butyl-3-aminopyrrolidine-1-carboxylate (1) was synthesized by starting from the
cheap natural amino acid, L-aspartic acid (Scheme 1). The amino group of L-aspartic
acid was first protected by benzyl chloroformate (Cbz-Cl) and sodium hydroxide in the
catalysis of the phase transfer catalyst (PTC) benzyl triethylammonium chloride to pro-
vide compound 2 in 86% isolated yield. We observed that the used loading of PTC was
critical to the reaction yield and product purity. The optimized amount of PTC was 2–3
mol%. Both the product yield and purity would decrease if the used PTC amount is
lower than 2%. The reaction temperature and pH value had similarly effect on the prod-
uct yield and purity. Therefore, a sodium hydroxide solution should be added to keep
the reaction pH value around 10–11. The reaction temperature should also be lower
ꢀ
than 15 C in order to obtain the highest yield of the product.
Then, esterification of compound 2 yielded compound 3 using acetyl chloride and
[
21]
methanol.
It should be noted that acetyl chloride should be added slowly to metha-
ꢀ
nol and the temperature should be kept below 10 C. The reaction mixture should be
neutralized with solid sodium bicarbonate after completion of the reaction. This treat-
ment can markedly minimize the by-products. Nearly, all the main side-products in this
step can be totally removed after washing the reaction mixture with a sodium

2
454
Z.-J. HAN ET AL
Scheme 1. Synthesis of (S)-1-Boc-3-aminopyrrolidine. Reagents and conditions: (i) benzylchlorofor-
mate, aq. NaOH, benzyltriethylammonium chloride, 86%; (ii) AcCl, MeOH, 90%; (iii) NaBH4, MeOH/THF,
9
0%; (iv) MsCl, triethylamine, ethyl acetate, 85%; and (v) liquid NH3, (Boc)2O, TEA, 65%; (vi) 10% Pd/
C, EtOH, 95%.
bicarbonate solution (10%) during work-up. The amount of acetyl chloride should be
1
.2–1.25 equivalent to the Cbz-protected aspartic acid 2 to enable the highest yield.
Reduction of 3 with sodium borohydride in the mixed solvents of methanol and
[
22]
tetrahydrofuran provided access to diol 4.
Notably, ethanol could also be the suitable
solvent in small scale in this reaction. However, ethanol made the reaction very slow in
large scale as compared to methanol. To gain a high yield, methanol must be slowly
ꢀ
added to maintain the reaction temperature below 10 C. The optimized amount of
sodium borohydride was 1.8–1.9 equivalent to the diester 3.
The order of adding the reaction material into the reaction flask was important dur-
ing the conversion of compound 4 to 5. The yield and product purity will be much bet-
ter by adding 4 and triethylamine into methanesulfonyl chloride than conversely. This
step is very exothermic and generates much energy. The reaction temperature, therefore,
ꢀ
need to be controlled strictly between 0 and 5 C by adding 4 and trimethylamine
slowly. The product purity can be significantly increased by washing the condensed
reaction mixture after completion of this step with methanol. This is an effective
method to improve the product purity because the solubility of compound 5 in metha-
nol is poor. It should be noted that the product is not stable in methanol for long time.
So, the washing action must be as quick as can and cooled methanol should be used.
The liquid phase could be recycled to recover compound 5 in washing and methanol
could be recovered readily by distillation.
Treatment of compound 5 with liquid ammonium successfully enabled the ring clos-
ure. Successively and directly introduction of tert-butoxycarbonyl anhydride readily
resulted in the biprotected compound 6 in moderate yield (65%) just in one pot.

V
R
SYNTHETIC COMMUNICATIONS
2455
Removing Cbz group off compound 6 quantitatively obtained target 3-aminopyrrolidine
by means of the traditional hydrogenation in the catalysis of 10% Pd/C in methanol.
1
Conclusion
In summary, we have successfully developed an economical synthetic route for 3-amino-
pyrrolidine 1 with high yield in each step. The reaction conditions were discussed in
details, and the steps could be scaled up to one hundred grams conveniently. The start-
ing material is inexpensive and the route is reliable. Therefore, this protocol is typical of
practicability and economy to the industrial synthesis of 3-aminopyrrolidine.
Experimental
[
23]
Tert-Butyl (S)-3-aminopyrrolidine-1-carboxylate (1).
In a 1-L round bottom flask, to
a stirred solution of 60 g compound 6 (0.187 mol, 1.0 eq.) in 300 mL of ethanol was
added 6 g of 10% Pd/C at room temperature. The mixture was stirred under 1 atm
hydrogen atmosphere overnight. The solid was filtered off and the filtrate was evapo-
rated under reduced pressure to give the crude product. The crude product was purified
using silica gel column chromatography eluted with CH Cl : MeOH = 20:1–15: 1 to
2
2
28
give the product as a yellow oil, yield 33.2 g, 95%.[a] -5.0 (c 1.0 in CHCl ); {Aldrich
Chemical [a]20 -2.0 (c 1.0 in CHCl )}; H NMR (600 MHz, DMSO-d ) d ppm:
D
3
1
D
3
6
3
.25–3.37 (m, 3H), 3.14–3.18 (m, 1H), 2.82–2.84 (m, 1H), 1.82–1.85 (m, 1H), 1.49–1.52
1
3
(m, 1H), 1.36 (s, 9H). C NMR (600 MHz, DMSO-d , mixture of two amidic isomers
6
1
4
:1) d ppm: 154.06, 154.01 (CO), 78.34 (C), 54.57, 54.27 (CH ), 51.39, 50.51 (CH),
2
4.65, 44.43 (CH ), 34.62, 33.88 (CH2), 28.62 (3xCH3). HRMS cacld for
2
þ
(C H N O þH) 187.1441, found 187.1442.
9
18 2 2
Disclosure statement
The authors confirm that this article content has no conflict of interest.
Funding
We are grateful to the National Natural Science Foundation of China (No. 81670594) and
Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital
(No. CY2017-MS05) for the financial support.
References
[
1] Barry, A. L.; Jones, R. N. J. Antimicrob. Chemother. 1989, 23, 527–535. DOI: 10.1093/jac/
3.4.527.
2
[2] Wang, Y.; Damu, G. L.; Lv, J. S.; Geng, R. X.; Yang, D. C.; Zhou, C. H. Bioorg. Med.
chem. Lett. 2012, 22, 5363–5366. DOI: 10.1016/j.bmcl.2012.07.064.
[
[
3] Syed, Y. Y. Drugs 2014, 74, 1523–1542. DOI: 10.1007/s40265-014-0273-x.
4] Koga, T.; Abe, T.; Inoue, H.; Takenouchi, T.; Kitayama, A.; Yoshida, T.; Masuda, N.;
Sugihara, C.; Kakuta, M.; Nakagawa, M.; et al. Antimicrob. Agents Chemother. 2005, 49,
3239–3250. DOI: 10.1128/AAC.49.8.3239-3250.2005.

2
456
Z.-J. HAN ET AL
[
5] Zhang, C.; Tan, C.; Zu, X.; Zhai, X.; Liu, F.; Chu, B.; Ma, X.; Chen, Y.; Gong, P.; Jiang, Y.
Eur. J. Med. Chem. 2011, 46, 1404–1414. DOI: 10.1016/j.ejmech.2011.01.020.
6] Lim, J. W.; Oh, Y.; Kim, J. H.; Oak, M. H.; Na, Y.; Lee, J. O.; Lee, S. W.; Cho, H.; Park,
W. K.; Choi, G.; Kang, J. Bioorg. Med. Chem. Lett. 2010, 20, 2099–2102. DOI: 10.1016/
j.bmcl.2010.02.072.
[
[7] Moree, W. J.; Kataoka, K.; Ramirez-Weinhouse, M. M.; Shiota, T.; Imai, M.; Tsutsumi, T.;
Sudo, M.; Endo, N.; Muroga, Y.; Hada, T.; et al. Bioorg. Med. Chem. Lett 2008, 18,
1869–1873., DOI: 10.1016/j.bmcl.2008.02.015.
[
[
8] Tomori, H.; Shibutani, K.; Ogura, K. Heterocycles 1997, 44, 213–225.
9] Rosen, T.; Chu, D. T.; Lico, I. M.; Fernandes, P. B.; Shen, L.; Borodkin, S.; Pernet, A. G. J.
Med. Chem. 1988, 31, 1586–1590. DOI: 10.1021/jm00403a017.
[
[
[
[
10] Andres, C. J.; Lee, P. H.; Nguyen, T. H.; Meyers, A. I. J. Org. Chem. 1995, 60, 3189–3193.
DOI: 10.1021/jo00115a040.
11] Moon, S.-H.; Lee, S. Synth. Commun 1998, 28, 3919–3926. DOI: 10.1080/
0
0397919808004949.
12] Maddaluno, J.; Corruble, A.; Leroux, V.; PI ꢀe , G.; Duhamel, P. Tetrahedron: Asymmetry
992, 3, 1239–1242. DOI: 10.1016/S0957-4166(00)82081-9.
1
13] Davies, S. G.; Garner, A. C.; Goddard, E. C.; Kruchinin, D.; Roberts, P. M.; Smith, A. D.;
Rodriguez-Solla, H.; Thomson, J. E.; Toms, S. M. Org. Biomol. Chem. 2007, 5, 1961–1969.
DOI: 10.1039/b704932c.
[
[
[
[
[
[
[
14] Flinois, K.; Yuan, Y.; Bastide, C.; Harrison-Marchand, A.; Maddaluno, J. Tetrahedron
2
002, 58, 4707–4716. DOI: 10.1016/S0040-4020(02)00377-0.
15] Sakurai, R.; Yuzawa, A.; Sakai, K. Tetrahedron: Asymmetry 2008, 19, 1622–1625. DOI:
0.1016/j.tetasy.2008.06.025.
16] Zhu, S.; Yu, S.; Wang, Y.; Ma, D. Angew. Chem. Int. Ed. Engl. 2010, 49, 4656–4660. DOI:
0.1002/anie.201001644.
17] Hoang, C. T.; Nguyen, V. H.; Alezra, V.; Kouklovsky, C. J. Org. Chem. 2008, 73,
162–1164. DOI: 10.1021/jo702278k.
1
1
1
18] Davies, S. G.; Garner, A. C.; Goddard, E. C.; Kruchinin, D.; Roberts, P. M.; Rodriguez-
Solla, H.; Smith, A. D. Chem. Commun. 2006, 2664–2666. DOI: 10.1039/b604835h.
19] Ashton, T. D.; Aumann, K. M.; Baker, S. P.; Schiesser, C. H.; Scammells, P. Bioorg. Med.
Chem. Lett. 2007, 17, 6779–6784. DOI: 10.1016/j.bmcl.2007.10.028.
20] Falgueyret, J. P.; Oballa, R. M.; Okamoto, O.; Wesolowski, G.; Aubin, Y.; Rydzewski,
R. M.; Prasit, P.; Riendeau, D.; Rodan, S. B.; Percival, M. D. J. Med. Chem. 2001, 44,
94–104. DOI: 10.1021/jm0003440.
[
21] Hern ꢀa ndez, J. N.; Mart ꢀı n, V. S. J. Org. Chem. 2004, 69, 3590–3592. DOI: 10.1021/
jo049759+.
[
[
22] Xie, X.; Stahl, S. S. J. Am. Chem. Soc. 2015, 137, 3767–3770. DOI: 10.1021/jacs.5b01036.
23] Shchekotikhin, A. E.; Glazunova, V. A.; Luzikov, Y. N.; Buyanov, V. N.; Susova, O. Y.;
Shtil, A. A.; Preobrazhenskaya, M. N. Bioorg. Med. Chem. 2006, 14, 5241–5251. DOI:
10.1016/j.bmc.2006.03.052.