A stereoselective, catalytic strategy for the in-flow synthesis of advanced precursors of rasagiline and tamsulosin

Article abstract of DOI:10.1016/j.bmc.2017.01.023

The diastereoselective, trichlorosilane-mediate reduction of imines, bearing different and removable chiral auxiliaries, in combination either with achiral bases or catalytic amounts of chiral Lewis bases, was investigated to afford immediate precursors of chiral APIs (Active Pharmaceutical Ingredients). The carbon-nitrogen double bond reduction was successfully performed in batch and in flow mode, in high yields and almost complete stereocontrol. By this metal-free approach, the formal synthesis of rasagiline and tamsulosin was successfully accomplished in micro(meso) flow reactors, under continuous flow conditions. The results of these explorative studies represent a new, important step towards the development of automated processes for the preparation of enantiopure biologically active compounds.

Full text of DOI:10.1016/j.bmc.2017.01.023

Accepted Manuscript
A stereoselective, catalytic strategy for the in-flow synthesis of advanced pre-
cursors of Rasagiline and Tamsulosin
Davide Brenna, Margherita Pirola, Laura Raimondi, Anthony J. Burke,
Maurizio Benaglia
PII:
S0968-0896(17)30089-5
DOI:
http://dx.doi.org/10.1016/j.bmc.2017.01.023
BMC 13502
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
24 December 2016
12 January 2017
14 January 2017
Please cite this article as: Brenna, D., Pirola, M., Raimondi, L., Burke, A.J., Benaglia, M., A stereoselective, catalytic
strategy for the in-flow synthesis of advanced precursors of Rasagiline and Tamsulosin, Bioorganic & Medicinal
Chemistry (2017), doi: http://dx.doi.org/10.1016/j.bmc.2017.01.023
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

A stereoselective, catalytic strategy for the in-flow synthesis of advanced
precursors of Rasagiline and Tamsulosin
Davide Brenna,a Margherita Pirola,a Laura Raimondi,a Anthony J. Burkeb and Maurizio Benagliaa**
b
aDipartimento di Chimica, Universita’ degli Studi di Milano, via Golgi 19, 20133 Milano, Italy; Department
of Chemistry and Chemistry Center of Évora, University of Évora, Rua Romão Ramalho, 59, 7000 Évora,
Portugal
*Corresponding author: Maurizio Benaglia, tel. +390250314171; fax: +390250314159; e-mail:
maurizio.benaglia@unimi.it.
Abstract: The diastereoselective, trichlorosilane-mediate reduction of imines, bearing different and
removable chiral auxiliaries, in combination either with achiral bases or catalytic amounts of chiral Lewis
bases, was investigated to afford immediate precursors of chiral APIs (Active Pharmaceutical Ingredients).
The carbon-nitrogen double bond reduction was successfully performed in batch and in flow mode, in high
yields and almost complete stereocontrol. By this metal-free approach, the formal synthesis of rasagiline
and tamsulosin was successfully accomplished in micro(meso) flow reactors, under continuous flow
conditions. The results of these explorative studies represent a new, important step towards the
development of automated processes for the preparation of enantiopure biologically active compounds.
Keywords: active pharmaceutical ingredients/ flow reactors/stereoselective synthesis / reduction / flow
chemistry / chiral amines / metal-free catalysis
1. Introduction
Rasagiline mesylate (Scheme 1), also known as (R)-(+)-N-propargyl-1-aminoindan mesylate, is a commer-
cially marketed pharmaceutically active substance, under the brand name azilect®. The racemic form of the
drug was patented by Aspro Nicholas in the early 1979, and was later found to be indicated for treat-
ment of Parkinson’s disease (PD), being effective both as monotherapy in early PD, and as adjunctive in
patients with advancing PD and motor fluctuations.[1] This chiral amine is a potent second-
generation

propargylamine pharmacophore that selectively and irreversibly inhibits the B-form of the
monoamineoxidase enzyme (MAO-B) over type A by a factor of fourteen.[2] European drug-regulatory
authorities approved this potent MAO-B inhibitor in February 2005 and the US FDA in May 2006.[3]
Although the S-(−)-enantiomer of N-propargyl-1-aminoindane still exerts some neuroprotective properties,
the potency of R-(+)-enantiomer against the MAO-B enzyme is approximately 1000-fold higher. Different
strategies aimed to the preparation of the enantiopure compound have been explored,[4] but, at the best
of our knowledge, a stereoselective organocatalytic approach for the preparation of rasagiline has never
been reported so far. We report here a metal-free stereoselective strategy for the synthesis of rasagiline
and of an advanced intermediate of another API, tamsulosin, sold under the trade name flomax as single
enantiomer. Active as antagonist for α1a adrenergic receptor, It is used to treat symptomatic benign
prostatic hyperplasia and to treat urinary retention. Starting from this common precursor, different
pharmaceutically active compounds could be prepared, having as biological targets different receptors such
as cholinesterase and monoamine oxidase inhibition [5], σ-receptors [6] and human adenosine A2A
receptor.[7]
The synthetic plan for the preparation of the two-target molecules involves a metal-free stereoselective
reduction of imines, easily prepared starting from commercially available ketones (Scheme 1).[8]
Scheme 1. Synthetic strategy for the synthesis of rasagiline and tamsulosin.
2. Results and Discussions
We initially explored the possibility to use a catalytic amount of chiral Lewis base (LB) for the
stereoselective, trichlorosilane-mediated reduction of the imine prepared starting from 1-indanone. Two
different chiral picolinamides, previously developed in our group, were tested.[9-10] Using ephedrine-
derived catalyst A, the chiral amines were obtained in high yields, both using PMP (paramethoxyphenyl)
and benzyl protected imines, but with modest enantioselectivities, up to 60%. e.e. for the (R)-enantiomer.

No better results were observed with catalyst type B, that is known to lead to the formation preferentially
of the (S)-isomer.[10]
Scheme 2. Enantioselective reductions of imines for the synthesis of rasagiline intermediates.
Then, we decided to explore the use of a chiral auxiliary, by employing α-methylbenzylamine as cheap and
readily removable element of stereocontrol in the reduction, that was already successfully employed in
previous works (Scheme 3).[8j] As achiral Lewis base, N,N-dimethyl formamide was selected as well
established, inexpensive and efficient activator of trichlorosilane for the reduction of ketoimines.[8j-9]
Scheme 3. Stereoselective reductions of chiral imines 3c/3d.
Reductions were performed starting from a diastereoisomeric mixture of imine 3, prepared from 1-(R)-
phenylethylamine in a 9:1 (3c:3d) ratio, in favor of the E imine 3c. The best results were achieved working
at -20°C, and performing the reaction for 36h; the product was obtained in 55% yield and 98:2
diastereomeric ratio in favor of the (R,R) stereoisomer 4c (Table 1, entry 5). To achieve complete

conversion higher reaction temperature were needed (Table 1, entry 6), leading to a small decrease of
diastereoselection (90:10 of d.r.).
Table 1. Reductions of chiral imine 3c/3d.
Entry
1
LB
DMF
DMF
DMF
DMF
DMF
DMF
A
T (° C)
0
t(h)
18
18
36
36
36
18
36
36
36
Conv. (%)a
d.r.b
67
44
42
77
55
98
90
20
80
90:10
90:10
90:10
90:10
98:2
2
-10
-10
0
3
4c
5c
-20
0 to rt
-20
-20
-20
6
90:10
90:10
76:24
>98:2
7d
8d
9d,e
B
B
c conversions were evaluated on H1-NMR, b d.r. were evaluated on crude mixtures using H1-NMR, c HSiCl3 was
further added every 12 hours, d reaction was performed using 0.15 eq. of chiral LB, e reaction was promoted
by the pseudoenantiomer of catalyst B.
Finally, in the attempt to increase further the efficiency of the process, the use of a match combination
between the chiral auxiliary and the chiral catalyst was investigated. Based on previous works,[9] we
selected the known favorable combination of catalyst A and 1-(R)-phenylethylamine as chiral auxiliary: the
reduction was accomplished in 90% conversion and a 90:10 of d.r. ratio (Table 1, entry 7). Since the use of
catalyst B, that leads to formation of products of (S) configuration,[10] afforded, as expected, the product
in lower stereoselectivity (entry 8, mismatch couple with the chiral auxiliary that favours the formation of
product with (R) configuration), the use of pseudo-enantiomer of catalyst B allowed to obtain the product
4c in 80% conversion and a complete diasteroselectivity (Table 2, entry 9).
With the best reaction conditions in our hands, we decided to explore the possibility of employing different
chiral auxiliaries. Since the removal of the α-methylbenzylamine tipycally requires palladium catalysts,[11]
we focused our attention onto the use of a chiral auxiliary removable without the need of precious
transition metals. In particular, we selected commercially available (R)-4-methoxy-α-methylbenzylamine
and (R)-2-methyl-2-propanesulfinamide since they could be removed under metal-free conditions.[12], [13]

Imines 5a and 6a were readily synthesized and their reduction was performed in the presence of 3.5 mol
eq. of trichlorosilane and stoichiometric amounts of DMF or catalytic amounts of chiral picolinamide A (see
Scheme 4).
Imine 5a was efficiently reduced using DMF as achiral LB (Table 2, entry 1), with high conversion (80 %) and
a complete diasteroselectivity. In order to increase the yield, the reaction was then performed in the
presence of catalyst A (Table 2, entry 2); complete conversion of the starting material into the chiral amine
5b and a total stereocontrol of the reaction were observed.
Scheme 4. Stereoselective reductions of chiral imines 5a-6a.
Table 2. Reduction of chiral imines 5a-6.
Entry
1a
2b
3 a
4c
Imine
5a
LB
DMF
A
Conv. (%)
d.r.
>98:2
>98:2
ND
80
98
<5
5a
6a
DMF
A
6a
99
80:20
a
b
c
5 eq. of DMF were used, 0.15 eq of catalys were used the product was obtained as primary amine
directly after the work up; e.e. was determined by HPLC on chiral column (see the Supporting Information)

Analogously, the reduction of imine 6a was efficiently promoted by catalyst A, affording the product 6b,
that was in situ deprotected during the basic aqueous work up, to afford the primary chiral amine 1 in
quantitative yield and 60% e.e. (entry 4, Table 2).
Considering the raising interesting for the flow preparation of API’s,[14] based on these results and with the
aim to further accelerate the reaction, we explored the possibility of developing a continuous flow
methodology for the preparation of rasagiline. Recently our group has demonstrated that HSiCl3-mediated
diastereoselective imine reduction could be efficiently performed in (micro)-mesoreactors under
continuous flow conditions.[15]
The experimental set up involves a coil-reactor, realized by using PTFE tubing (1.58 mm outer diameter,
0.58 mm inner diameter, 1.89 m length, 500 μL effective volume) coiled in a bundle and immersed in a bath
cooled to the desired temperature. A syringe pump, equipped with two Hamilton gastight syringes, fed the
solution containing the imine and the Lewis base dissolved in DCM, and the solution of trichlorosilane in
DCM through a T-junction into the coil-reactor (Scheme 5).
Scheme 5. Continuous flow preparation of an advanced precursor of rasagiline.
Running the reduction of imine 5a at low temperature (17°C), low conversions were detected; when the
reaction was performed at 30°C, the product was isolated in 83% yield but, as expected, with a lower
disatereoisomeric ratio (92:8, entry 4, Table 3). In order to achieve a complete stereocontrol, the reaction
was run in the flow reactor in the presence of catalyst A; operating at 30°C and with a 30 min. residence
time, the matching combination of an enantiopure catalyst with the chiral auxiliary, the chiral amine 5b was
in continuo produced in 70% yield as stereoisomerically pure compound (entry 5, Table 3).
Table 3. In-flow synthesis of an advanced intermediate of rasagiline.
Entry
LB
Imine
T (° C)
Residence
Eq.
Conv. (%)
d.r.

time (min.)
1
2
3
4
5
DMF
DMF
DMF
DMF
A
5a
5a
5a
5a
5a
17
17
17
30
30
10
20
30
20
20
5
5
20
34
35
83
70
98:2
98:2
98:2
92:8
>98:2
5
5
0.2
The synthesis of an advanced intermediate of tamsulosin was then studied. By following the same synthetic
approach and taking advantage of the previously used chiral auxiliaries, enantiopure imines 7a and 8a were
synthesized and their reduction studied in batch (Scheme 6).
Scheme 6. In batch synthesis of advanced precursors of tamsulosin.
The results are reported in Table 4; when using an achiral base (DMF), the reduction of imine 7a proceeds
with a modest diastereoselectivity, and only with catalyst B an improved stereocontrol was obtained,
although the product was isolated in 50% yield only. However, starting from chiral imine 8a better results
were achieved; simply using a combination of two very cheap reagents, like trichlorosilane and N,N-
dimethylformamide, the primary amine 2 was directly obtained after the work up in quantitative yield and
94% e.e. (entry 9, Table 4).
Table 4. In batch synthesis of tamsulosin precursor
Entry
1a
2b
LB
Imine
7a
Eq.
5
Conv. (%)
d.r.
DMF
DMF
99
99
65:35
70:30
7a
5

3
4
DMF
A
7a
7a
7a
8a
8a
8a
5
99
<5
50
<5
45
99
77:23
n.d.
0.15
0.15
0.15
0.15
0.15
6
B
92:8
n.d.
7
A
8
9c
B
n.d.
93:7c
DMF
a reaction performed from 0°C to room temperature, b reaction performed at 0°C, c the product was obtained
as primary amine directly after the work up; e.e. was determined by HPLC on chiral column (see the
Supporting Information)
The reaction was then performed in the previously described flow reactor system (Scheme 7); with imine
7a the in-flow reduction nicely reproduced the results of the in batch procedure (entries 1-2, Table 5);
interestingly, it was possible to achieve the removal of the chiral auxiliary under continuous flow
conditions, as shown in eq.A of Scheme 5. The continuous hydrogenolysis of chiral amines was performed
with a ThalesNano H-Cube Mini™, equipped with a 10% Pd/C cartridge; at 50 °C and 50 bar, after 1 hour,
chiral amine 2 was obtained in quantitative yield.
Scheme 7. In-flow synthesis of chiral amine 2, a tamsulosin precursor.
When enantiopure imine 8a was reduced with DMF and trichlorosilane in the PTFE flow reactor, the chiral
primary amine 2 was directly produced and was collected out from the flow reactor, after in line basic
aqueous work up, in 70% isolated yield and 88% e.e. (entries 3-4, Table 5).
Table 5. Continuous flow reduction of chiral imines 7a and 8a.

Residence
Entry
LB
Imine
Eq.
Conv. (%)
d.r.
time (min.)
1
2
3a
4a
B
7a
7a
8a
8a
20
30
20
30
0.2
0.2
5
60
75
60
70
92:8
92:8
94:6a
94:6a
B
DMF
DMF
5
a the product was obtained as primary amine directly after the work up; e.e. was determined by NMR with
chiral shift-agents (see the Supporting Information)
3. Conclusions
In the present study, a stereoselective, metal-free strategy for the synthesis of chiral amines, direct
precursors of rasagiline and tamsulosin, was developed. After setting up the reaction conditions in batch,
the stereoselective trichlorosilane-mediated reduction of chiral imines was efficiently performed under
continuous flow conditions. Chiral primary amines were obtained either by a continuous flow
hydrogenolysis, or directly out from the flow reactor after an in-line aqueous work up, depending on the
chiral auxiliary group at the amine nitrogen atom.
The present work represents a further step towards the development of a multistep continuous flow
process for the synthesis of enantiomerically pure pharmaceutically relevant amines.
4. Aknowledgements
DB thanks Università degli Studi di Milano for a Ph.D. fellowship; MB thanks CNR for the bilateral project
FCT/CNR 2015-2016 (Ref. 441.00) “Exploring novel organocatalytic enantioselective reductions for
accessing key drugs for Neurodegenerative disease treatment”. AJB thanks bilateral project FCT/CNR 2015-
2016 (Ref. 441.00).
5. References
1- a) Sudhir, M. S.; Nadh, R.V Drug Invent. Today, 2013, 5, 133–138. b) Fernández, M.; Negro, S.; Slowing, K.;
Fernández-Carballido, A.; Barcia, E. Int. J.Pharm., 2011, 271–280. c) Weinreb, O.; Amit, T.; Riederer, P.;
Youdim, M.B.H.; Mandel, S.A. in: International Review of Neurobiology, Academic Press: NewYork, 2011. pp.
281.
2- Fernández, M.; Barcia, E.; Fernández-Carballido, A.; Garcia, L. Slowing, K.; Negro, S. Int. J. Pharm., 2012, 266–
278.

3- Guay, D.R.P.; Am. J. Geriatr. Pharmacother. 2006, 330–346.
4- For selected examples of kinetic resolution see: a) Selic, L. WO Patent 064 216, 2011, to LEK Pharmaceuticals.
b) Thanedar, A.A.; Deshmukh, S.A. Zope, S.S.; Kelkar, L.M.; Koilpillai, J.P.; Gajera, J.M. WO Patent 048 612,
2011, to Glenmark Generics Limited. For selected examples of enzymatic preparation see: c) Malik, M.S.;
Park, E-S.; Shin, J-S Green Chem., 2012, 14, 2137–2140. d) Ma, G.; Xu, Z.; Zhang, P.; Liu, J.; Hao, X.; Ouyang, J.;
Liang, P.; You, S.; Jia, X. Org. Process Res. Dev., 2014, 5, 1169–1174. For catalytic and stereoselective metal
based methodologies see: e) Brunner, H.;. Becker, R; Gauder, S. Organometallics, 1986, 5, 739–746. f) Takei,
I.; Nishibayashi, Y.; Ishii, Y.; Mizobe, Y.; Uemura, S.; Hidai, M. Chem. Commun., 2001, 44, 2360–2361. For
selected examples of the use of chiral auxiliary see: g) Gutman, A.L.; Etinger, M.; Nisnevich, G.; Polyak, F.
Tetrahedron Asymm., 1998, 9, 4369–4379. h) Colyer, J.T.; Andersen, N.G.; Tedrow, J.S.; Soukup, T.S.; Faul,
M.M. J. Org. Chem., 2006, 7, 6859–6862.
5- Lu, C.; Zhou, Q; Yan, J.; Du, Z.; Huang, L.; Li, X Eur. J. of Med. Chem., 2013 , 62, 745-753.
6- Glennon, R., A.; Ismaiel, M.; Smith, J., D.; Yousif, M.; El-Ashmawy, M.; Herndon, J. L.; Fischer, J. B.; Howie, K. J.
B.; Served, A. C. J. Med. Chem., 1991, 34, 1855-1859.
7- Bosch, M. P.; Campos, F.; Niubo´, I.; Rosell, G.; Dìaz, J. L.; Brea, J.; Loza, M., I.; Guerrero, A. J. Med. Chem.,
2004, 47, 4041-4053.
8- For reviews on organocatalyzed enantioselective reductions see: a) Benaglia, M.; Genoni, A.; Bonsignore, M.
Enantioselective organocatalytic reductions in Stereoselective Organocatalysis: From C-C to C-heteroatom
bond formation, (Ed. R. Rios Torres) Wiley, 2012; b) Rossi, S.; Benaglia, M.; Massolo, E.; Raimondi, L. Catal.
Science Technol. 2014, 9, 2708-2723. Reviews on HSiCl3-mediated reductions: c) Guizzetti, S.; Benaglia, M.
Eur. J. Org. Chem., 2010, 5529-5541; d) Jones, S.; Warner, C. J. A. Org Biomol. Chem., 2012, 10, 2189-2200.
For representative metal-catalyzed reductions of N-1-phenylethyl imines see: e) Eleveld, M. B.; Hogeveen, H.;
Schudde, E. P. J. Org. Chem., 1986, 51, 3635-3638; f) Ranu, B. C.; Sarkar, A.; Majee, A. J. Org. Chem., 1997, 62,
1841-1842; g) for a recent contribution on a sequential reductive amination-hydrogenolysis see Nugent, T. C.;
Negru, D. E.; El-Shazly, M.; Hu, D.; Sadiq, A.; Bibi, A. Adv. Synth. Catal., 2011, 353, 2085–2092 and references
cited; for organocatalytic reductions of chiral imines, see: h) Farrell, J. M.; Heiden, Z. M.; Stephan, D. W.
Organometallics, 2011, 30, 4497-4500. J) Guizzetti, S.; Benaglia, M.; Biaggi, C.; Celentano, G. Synlett 2010,
134-136.
9- Guizzetti, S.; Benaglia, M.; Rossi, S. Org. Lett., 2009, 11, 2928-2932.
10- Barrulas, P. C.; Genoni, A.; Benaglia, M.; Burke, A. J. Eur. J. Org. Chem. 2014, 7339-7442.
11- Gutman, A., L.; Etinger, M.; Nisnevich, G.; Polyak, F. Tetrahedron: Asymmetry , 1998, 9, 4369–4379.
12- Astellas Pharma Inc., Patent: US2014/88080 A1, 2014.
13- Colyer, J.T. ; Andersen, N.G.; Tedrow, J.S.; Soukup, T.S.;Faul, M.M. J. Org. Chem., 2006, 71, 6859–6862.
14- Review: Porta, R.; Benaglia, M.; Puglisi, A. Org. Process Res. Dev., 2016, 20, 2-25.
15- a) Brenna, D.; Benaglia, M.; Porta, R.; Fernandes, S.; Burke, A., J. Eur. J. Org. Chem., 2016,
DOI:10.1002/ejoc.201601268; for a pioneer work in the field of in-flow imine reduction see b) Saaby, S.;
Knudsen, K.R.; Ladlow, M.; Ley, S. V. Chem. Commun., 2005, 2909–2911; for recent reviews: c) Lange, H.;
Carter, C. F.; Hopkin, M. D.; Burke, A.; Goode, J. G.; Baxendale, I. R.; Ley, S. V. Chem. Sci. 2011, 2, 765–769; d)
Irfan, M.; Glasnov, T. N.; Kappe, C. O. ChemSusChem. 2011, 4, 300-316.

Graphical abstract