Practical synthesis of an orally active renin inhibitor aliskiren

Article abstract of DOI:10.1016/j.tetlet.2005.07.028

A convergent synthesis of aliskiren was accomplished via the use of Segment AB as the key intermediate, which was prepared via the coupling of the Grignard reagent derived from Segment B with Segment A, followed by subsequent oxidative lactonization.

Full text of DOI:10.1016/j.tetlet.2005.07.028

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6337–6340
Practical synthesis of an orally active renin inhibitor aliskiren
Hua Dong, Zhi-Liu Zhang, Jia-Hui Huang, Rujian Ma,* Shu-Hui Chen and Ge Li
WuXi PharmaTech Co., Ltd, No. 1 Building, 288 FuTe ZhongLu, WaiGaoQiao Free Trade Zone, Shanghai 200131, PR China
Received 19 May 2005; revised 6 July 2005; accepted 8 July 2005
Available online 28 July 2005
Abstract—A convergent synthesis of aliskiren was accomplished via the use of Segment AB as the key intermediate, which was pre-
pared via the coupling of the Grignard reagent derived from Segment B with Segment A, followed by subsequent oxidative
lactonization.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
derived from the coupling of Segment B (via its Grig-
nard reagent) and Segment A followed by a subsequent
lactonization. We further envisioned that the opening of
Segment AB with Segment C should provide the desired
aliskiren (Scheme 1).
The renin-angiotensin system (RAS) plays a central role
in the regulation of blood pressure as well as in the
maintenance of sodium and electrolyte balance. Thus,
intervention of this cascade has been investigated as a
treatment option for hypertension and congestive heart
failure.1,2 Since the formation of the end product of
RAS, vasoconstrictor angiotensin II, is accomplished
through two enzymatic events mediated, respectively,
by renin (functioned at the first rate-limiting step)
and angiotensin-converting enzyme (ACE), it is thus
believed that inhibition of renin or ACE may result in
antihypertensive effects. Furthermore, given the fact that
angiotensinogen is the only known naturally occur-
ring substrate for renin (in contrast to the multiple sub-
strates known for ACE), this has rendered renin as an
ideal target for the development of antihypertensive
drugs.3
2. Synthesis of Segment A
The general synthetic route employed for this piece was
based on an approach reported by Goschke and Mail-
baum along with PharmaTechÕs modifications. As
shown in Scheme 2, with the intention to devise a prac-
tical and cost-efficient synthesis for aliskiren, we
replaced several expensive reagents used by Maibaum
and his collaborators and streamlined the overall
synthetic operations. Toward these goals, O-alkylation
of the phenolic hydroxyl group in 1 (at 400 g scale) with
the three-carbon side chain mesylate 2 (prepared from
its corresponding alcohol) gave rise to aldehyde 3
(98%), which was reduced with NaBH4 in ethanol to
provide the corresponding alcohol 4. PBr3 mediated
bromination of 4 led to the desired Segment E (91%
from 3), which was allowed to react with the lithium
enolate derived from EvanÕs chiral auxiliary 5 to afford
adduct 6 in 76% yield. Standard alkaline peroxide
mediated hydrolysis of 6 yielded the desired acid 7
(81%), which was further converted to the correspond-
ing alcohol 8 via LAH reduction in almost quantitative
yield. Subsequent treatment of 8 with PPh3/NBS led to
Segment D in 97% yield (at 460 g scale). Asymmetric
alkylation of the lithium enolate derived from 9 with
Segment D provided the expected product 10 (68%),
which was further elaborated into its corresponding
amino acid 11 via acidic hydrolysis. Compound 11 was
Aliskiren (also known as CGP60536B and SPP-100B)
was discovered by Novartis Pharma AG as a non-pep-
tidic orally active renin inhibitor after intensive research
for many years.4–6 Several recent publications detailed a
number of approaches toward the synthesis of aliski-
ren.7–11 Prompted by its fascinating biological activity
and structural complexity, we became interested in the
total synthesis of aliskiren.12 In this letter, we report a
convergent synthetic approach featuring Segment AB
as the key intermediate, which was envisioned to be
*
Corresponding author. Tel.: +86 21 5046 1111; fax: +86 21 5046
3718; e-mail: marj@pharmatechs.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.028

6338
H. Dong et al. / Tetrahedron Letters 46 (2005) 6337–6340
OH
H
H2N
NH2
7
5
1
O
O
O
N
NH2
2
4
NH2
6
O
3
O
O
Segment C
Aliskiren
+
O
O
O
Br
O
O
O
NHBoc
Segment B
Segment AB
+
O
O
O
O
O
Br
Br
O
O
O
O
O
NHBoc
Segment E
Segment D
Segment A
Scheme 1. PharmaTechÕs strategy for the synthesis of aliskiren.
HO
CHO
O
O
R
iv
O
O
O
i
iii
Br
O
O
H3CO
O
OMs
O
2
N
O
1
5
3
4
R = CHO
R = CH2OH
ii
Segment E
Bn
O
O
viii
O
O
O
R
O
O
O
v
vii
O
O
O
Br
N
O
9
EtO
Bn
N
Segment D
7
8
R = CO2H
R = CH2OH
6
N
vi
OEt
EtO
RHN
R'
N
N
O
O
O
O
O
O
OEt
xii
O
ix
O
O
NHBoc
O
11 R = H, R' = CO2Et
12 R = Boc, R' = CO2Et
13 R = Boc, R' = CH2OH
x
10
Segment A
xi
Scheme 2. Synthesis of Segment A: (i) K2CO3, CH3CN, 98%; (ii) NaBH4, EtOH; (iii) PBr3, CH2Cl2, 91% (two steps); (iv) 5, LiHMDS, THF, then
Segment E, 76%; (v) LiOH, H2O2, 81%; (vi) LAH, THF, 95%; (vii) PPh3, NBS, CH2Cl2, 97%; (viii) 9, n-BuLi, then Segment D, 68%; (ix) HCl, MeCN;
(x) Boc2O, Et3N; (xi) NaBH4, EtOH, 91% (three steps); (xii) DMSO, ClC(O)C(O)Cl, Et3N, CH2Cl2, 89%.
later converted to 12 (via N-Boc protection), thereafter
13 (via ester reduction) with an overall yield of 91%
(three steps from 10). The final Swern oxidation of 13
thus afforded the desired aldehyde Segment A in 89%
yield.
work-up and subsequent LAH reduction, compound
16 was converted to alcohol 18 through its acid interme-
diate 17 in an overall yield of 71%. Treatment of 18 with
NBS and triphenyl phosphine thus afforded the desired
bromo-derivative Segment B. It is worthwhile to men-
tion that this reaction sequence was scaled up to pro-
duce 300 g of Segment B.
3. Syntheses of Segments B and C
As also depicted in Scheme 3, Segment C was prepared
via a four-step sequence consisting of (1) C-methylation,
(2) LAH mediated cyano reduction, (3) N-Cbz protec-
tion (for easy purification), and (4) Pd(OH)2/C pro-
moted N-deprotection. The overall yield of this
sequence was quite low, this was primarily due to prod-
uct loss occurred during isolation.
In accordance with the synthetic routes outlined in
Scheme 3, benzyl alcohol 14 was first converted to its
chloromethyl ether 15 (33%), which was engaged in
the asymmetric C-alkylation with the titanium enolate
derived from 5 to yield the desired adduct 16 in 50%
yield. Upon standard alkaline peroxide mediated

H. Dong et al. / Tetrahedron Letters 46 (2005) 6337–6340
6339
O
O
ii
v
R
iii
R
O
Br
O
O
BnO
N
O
O
O
N
O
Bn
16
Segment B
5
17 R = CO H
14 R = H
15 R = CH Cl
2
iv
ix
Bn
i
18 R = CH OH
2
2
O
O
CN
vii, viii
vi
H2N
NH2
NC
CONH2
CbzHN
NH2
CONH2
20
21
19
Segment C
Scheme 3. Synthesis of Segments B and C: (i) HCHO, HCl (g), 33%; (ii) 5, TiCl4, CH2Cl2, then 15, 50%; (iii) LiOH, H2O2, 82%; (iv) LAH, THF,
86%; (v) PPh3, NBS, CH2Cl2, 61%; (vi) NaOEt, MeI, 64%; (vii) LAH, THF; (viii) CbzCl, Et3N; (ix) Pd(OH)2/C, H2, 20% (three steps).
4. Final assembly of aliskiren
oxidation of diol 23 yielded the corresponding lactone
24 (38%) with all four chiral centers (at C-2, C-4, C-5,
and C-7) correctly established. Further reaction of 24
with Segment C in the presence of 2-hydroxypyridine
and triethylamine gave rise to the desired adduct 25
in 65% yield. Upon N-deprotection and final salt
formation, compound 25 was converted to the target
product aliskiren fumarate salt in 80% overall yield for
two steps.
As shown in Scheme 4, treatment of Segment A (alde-
hyde) with the Grignard reagent prepared from Segment
B provided two diastereoisomers, 22b and 22a in a ratio
of 5:2 favoring the desired beta-isomer 22b. Upon O-
debenzylation and C-4 isomer separation, we obtained
the pure desired diastereomer (at C-4 position) 23 in
23% yield. The following TPAP/NMMO mediated
OH
OH
BocHN
O
4
O
O
O
OH
O
O
O
OBn
i
ii, iii
O
O
NHBoc
NHBoc
O
distereoselectivity β/α = 5:2
22β & 22α
23
Segment A
OH
4
NHR
HOOC
H
N
O
O
O
O
NH2
O
v, vi
iv
O
O
O
O
O
NHBoc
COOH
n
24
25 R = Boc, n = 0
Aliskiren-salt R = H, n = 0.5
Scheme 4. Synthesis of aliskiren: (i) Mg, Segment B; (ii) Pd(OH)2/C, H2; (iii) C-4 hydroxy isomer separation; 23% for 23; (iv) TPAP, NMMO, 38%;
(v) Segment C, 2-hydroxypyridine, Et3N, 65%; (vi) 0.33 N TMSCl, 1 N Phenol, CH2Cl2; (vii) HO2CCH@CHCO2H (trans), MeOH, 80%.
O
O
Boc
BocHN
O
Ph
N
O
N
N
LiOH, aq. MeOH
NaH, BnBr
LAH, THF
O
O
O
O
O
O
12
EDCI, HOBt
MeHNOMe-HCl
26 (70%)
27 (80%)
Top face attack
H
Boc
N
Ph
OH
BnO
Br
O
Segment B
Pd(OH)2/C
H2 (50Psi)
O
O
OBn
O
O
N
Mg
OH
O
Boc
Bn
O
29
28 (96%)
OH
4
OH
H
4 steps (20%)
O
O
O
N
NH2
O
O
O
NH2
O
O
NHBoc
see Scheme 4
30 (30% for 2 step)
4-epi-Aliskiren
Scheme 5. Synthesis of 4-epi aliskiren.

6340
H. Dong et al. / Tetrahedron Letters 46 (2005) 6337–6340
System. In The Renin-Angiotensin System; Johnson, J. A.,
5. Synthesis of 4-epi-aliskiren
Anderson, R. R., Eds.; Plenum Press: New York, 1980, pp
1–27.
In contrast to the low selectivity obtained for 22
(Scheme 4), treatment of N-bis-protected aldehyde 28
(prepared from 12 via a four-step sequence outlined in
Scheme 5) with the Grignard reagent derived from Seg-
ment B afforded a single C-4 isomer 29 (via Cram–Felkin
mode), which was converted to diol 30 via Pd(OH)2/C
mediated hydrogenation. Following the same reaction
sequence as described for 23 shown in Scheme 4, com-
pound 30 was converted to the 4-epi-aliskiren.
3. Greenlee, W. J. Med. Res. Rev. 1990, 10, 173–236.
4. Goeschke, R.; Rasseti, V.; Cohen, N. C.; Rahuel, J.;
Grutter, M.; Stutz, S.; Fuhrer, W.; Wood, J.; Maibaum, J.
15th Int. Symposium Med. Chem., 6–10 September,
Edinburgh, 1998, Abst. p 229.
5. Maibaum, J. et al. 15th Int. Symposium Med. Chem., 6–10
September, Edinburgh, 1998, Abst. p 230 and 231.
6. Rahuel, J.; Rasetti, V.; Maibaum, J., et al. Chem. Biol.
2000, 7, 493–504.
7. Mealy, N. E.; Castaner, J.; Castaner, R. M.; Silverstre, J.
Drugs Fut. 2001, 26, 1139–1148.
8. Rueger, H.; Stutz, S.; Goschke, R.; Spindler, F.; Mai-
baum, J. Tetrahedron Lett. 2000, 41, 10085–10089.
9. Sandham, D. A.; Taylor, R. J.; Carey, J. S.; Fassler, A.
Tetrahedron Lett. 2000, 41, 10091–10094.
In summary, we have devised a new convergent route
for the total synthesis of aliskiren and 4-epi-aliskiren.
Since all of the key building blocks could be prepared
in large scale, the synthetic route discussed herein may
be used as a practical route for the synthesis of aliskiren.
10. Dondoni, A.; De Lathauwer, G.; Perrone, D. Tetrahedron
Lett. 2001, 42, 4819–4823.
11. Goschke, R.; Stutz, S.; Heinzelmann, W.; Maibaum, J.
Helv. Chim. Acta 2003, 86, 2848–2870.
References and notes
12. Dong, H.; Zhang, Z-L.; Huang, J-H.; Chen, S. H.; Li, G.
Practical Synthesis of Aliskiren: An Orally Active Human
Renin Inhibitor. 230th ACS National Meeting in Wash-
ington DC. Abst.# MEDI-893844; August 28–September
1, 2005.
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Physiol. 1978, 40, 377–410.
2. Skeggs, L. T.; Doven, F. E.; Levins, M.; Lentz, K.;
Kahn, J. R. The Biochemistry of the Renin–Angiotensin