A new synthesis of the orally active renin inhibitor aliskiren

Article abstract of DOI:10.1016/j.tetlet.2011.06.056

A convergent synthesis of the orally active renin inhibitor aliskiren (1) is described. The synthesis was accomplished in 12 steps starting from the known chloride 2. The key step involves the Curtius rearrangement of the advanced intermediate 15, which provides lactone/carbamate 17 containing the correct stereochemistry and all of the functionality required for the preparation of the drug substance.

Full text of DOI:10.1016/j.tetlet.2011.06.056

Tetrahedron Letters 52 (2011) 4349–4352
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A new synthesis of the orally active renin inhibitor aliskiren
⇑
Joel Slade, Hui Liu, Mahavir Prashad, Kapa Prasad
Process Research and Development, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A convergent synthesis of the orally active renin inhibitor aliskiren (1) is described. The synthesis was
accomplished in 12 steps starting from the known chloride 2. The key step involves the Curtius rear-
rangement of the advanced intermediate 15, which provides lactone/carbamate 17 containing the correct
stereochemistry and all of the functionality required for the preparation of the drug substance.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 2 May 2011
Revised 8 June 2011
Accepted 13 June 2011
Available online 2 July 2011
Aliskiren (SPP100, TekturnaÒ) has recently received marketing
approval and was launched as the first orally active non-peptidic
renin inhibitor. This compound was discovered after an intensive
research effort.1–3 Recently, a number of publications have ap-
peared describing a variety of different approaches to the synthesis
of this compound.4–12 Prompted by these reports as well as the
interesting and useful biological activity, we undertook a new syn-
thetic approach involving the introduction of the amino group at
the 5-position with the desired stereochemistry via a Curtius rear-
rangement of 15 (Scheme 1) as the key step.
Synthesis of intermediate 5
The synthesis of 5 was efficiently carried out starting from the
readily available chloride8 2 using the malonic ester synthesis
(Scheme 2). The reaction of 2 with diethyl malonate in NaOEt/EtOH
O
MeO
O
MeO
O
Cl
OH
Me
Me
MeO
Me
Me
MeO
2
5
O
O
O
N
O
H
Me
Me
8
O
Me
Me
Me
Me
HO
Me
Me
Me
Me
O
H
N
6
1
5
NH2
2
Me
4
Me
7
3
MeO
O
MeO
O
O
O
NH2
O
OH
MeO
MeO
1
15
Scheme 1. Strategy for the Synthesis of aliskiren.
⇑
Corresponding author.
E-mail address: joel.slade@novartis.com (K. Prasad).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.056

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J. Slade et al. / Tetrahedron Letters 52 (2011) 4349–4352
was sluggish and required the addition of sodium iodide to proceed
to completion. The diester 3 was obtained as oil. Conversion to the
acid was carried out in two steps. First, the diester was decarbox-
ylated to the mono ester 4 using KOAc/DMSO/water.13 Following
an aqueous work up, 4 was saponified with sodium hydroxide to
5 in an overall yield of 30% for the three steps.
The alkylation proceeded smoothly to afford 7 with >99% diaste-
reomeric purity.15 For the oxidation step,16 the reaction was car-
ried out initially at 0 °C for 3 h, followed by warming to 20 °C
overnight. The yield of 8 was 57% over two steps.
Synthesis of intermediate 15 and the construction of aliskiren
Synthesis of intermediate 8
We envisioned joining 5 and 8 via an asymmetric anti-aldol
reaction using the norephedrine-derived chiral auxiliary 10 intro-
duced by Masamune.17 This reagent had been successfully em-
ployed in the enantioselective anti-aldol processes.18 Formation
of the ester 11 was very slow under Masamune’s conditions
The synthesis of 8 is shown in Scheme 3. Compound 6 was pre-
pared in greater than 95% yield from the corresponding oxazolidi-
none and isovaleryl chloride according to the procedure of Evans.14
MeO
MeO
O
MeO
O
COOEt
COOEt
CH2(CO2Et)2
Cl
NaI
NaOEt
37%
Me
Me
Me
Me
Me
Me
MeO
MeO
3
2
5
KOAc/DMSO/H2O
O
O
NaOH
OH
COOEt
MeO
O
HCl
MeO
70% (2 steps)
Me
Me
MeO
4
Scheme 2. Synthesis of intermediate 5.
O
O
O
Me
O
O
O
NaIO4
N
N
Me LiN(TMS)2
Br
N
CHO
Me
O
O
O
OsO4 (cat)
Me
Me
Me
57% (over 2 steps)
6
7
8
Scheme 3. Synthesis of intermediate 8.
O
OH
MeO
O
O
O
N
O
S
O
Me
CH3
Me
Me
MeO
Me
Me
MeO
O
Cl
O
5
10
N
Me
S
SOCl2
Me
MeO
Me
O
Me
Pyridine
9
Me
Me
Me
Me
O
Me
OH
11
8
Me
N
O
MeO
O
O
O
O
Me
MeO
O
S
N
O
Me
Me
12
Me
Scheme 4. Preparation of aldol product 12.

J. Slade et al. / Tetrahedron Letters 52 (2011) 4349–4352
4351
(Scheme 4). However, treatment with an additional 5 equiv of pyr-
idine and heating at 40 °C for 12 h afforded ester 11 in 47% yield
(purity 99.5%) after column chromatography. Ester 11 was treated
with dicyclohexylboron triflate and triethylamine at À78 °C, fol-
lowed by aldehyde 8 at À78 °C. The reaction was briefly brought
to 0 °C and monitored by HPLC. A second portion of 8 was added
O
Me
Me
OLi
Me
Me
Me
OH
Me
O
O
Me
Me
MeO
O
O
MeO
H
O
O
S
O
O
S
LiOOH
12
MeO
MeO
O
O
N
O
N
O
Me
Me
Me
Me
Me
Me
13
14
LiOH
O
Me
Me
O
Me
Me
MeO
O
O
OH
MeO
15
Scheme 5. Preparation of intermediate 15.
O
Me
Me
Me
Me
O
DPPA/Et3N
Toluene
15
MeO
O
N
20 °C, 20 m
65 °C, 60 m
C
O
MeO
16
BnOH
65 °C, 90 min
80%
O
O
Me
Me
Me
OH
Me
O
Me
O
Me
O
Me
Me
MTBE, 65 °C
H
N
NH2
Me
O
66%
Me
MeO
HN
BnO
MeO
O
HN
O
Me
O
Me
MeO
BnO
MeO
H2N
NH2
N
OH
19
17
18
H2, Pd/C
97%
HO
Me
Me
Me
Me
OH
Me
O
Me
Me
Me
Me
H
MeO
O
HN
O
N
NH2
O
Me
N
Me
MeO
MeO
O
NH2
O
Me
O
NH2
MeO
1
20
Scheme 6. Preparation of aliskiren.

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J. Slade et al. / Tetrahedron Letters 52 (2011) 4349–4352
to consume the remaining ester 11. The crude aldol product 12 (dr
>99:1) was used in the next step.
Acknowledgments
Evans’ auxiliary was easily cleaved with lithium hydroperox-
ide,19–21 while cleavage of Masamune’s auxiliary from 12 was more
difficult (Scheme 5).22 When a solution of 12 in THF and water was
treated with LiOH in the presence of H2O2, an exotherm was ob-
served, and the Evans’ auxiliary was completely gone within
15 min to form the lithium salt 13. Upon acidic work up, lactone
ester 14 was formed. Compound 14 was isolated in 83% yield after
chromatography. Reductive cleavage of the ester group of 14 with
hydrogen/Pd(OH)2/C was unsuccessful. However, heating 14 with
LiOH in dioxane/water at 40 °C for 5 days gave intermediate 15
in 53% yield after chromatography.
We thank Drs. Oljan Repic and Gerhard Penn for various sugges-
tions and helpful discussions during this work.
References and notes
1. Goeschke, R.; Rassetti, V.; Cohen, N. C.; Rahuel, J.; Grutter, M.; Stutz, S.; Fuhrer,
W.; Wood, J.; Maibaum, J. 15th International Symposium Medicinal Chemistry,
6–10 September, 1998, Edinburgh, Abst. p 229.
2. Rahuel, J.; Rasetti, V.; Maibaum, J., et al Chem. Biol. 2000, 7, 493–504.
3. Maibaum, J. et al. 15th International Symposium Medicinal Chemistry, 6–10
September, 1998, Edinburgh, Abst. p 230 and 231.
4. Dong, H.; Zhang, Z.-L.; Huang, J.-H.; Ma, R.; Chen, S.-H.; Li, G. Tetrahedron Lett.
2005, 46, 6337–6340.
To convert the carboxylic acid group into the amine, the Curtius
rearrangement of 15 was investigated. Azide formation with
diphenylphosphoryl azide (DPPA) had been applied to lactone-con-
taining carboxylic acids.23 Formation of the isocyanate 16 was car-
ried out in toluene/triethylamine and was nearly quantitative.
Addition of benzyl alcohol and heating at 65 °C for 90 min afforded
an 80% yield of the desired benzyl carbamate 17 after chromatog-
raphy. At this point, only two steps remained for completion of the
synthesis, ring opening with amino amide 18, followed by cleavage
of the carbamate. The ring opening did not take place in the ab-
sence of 2-hydroxypyridine.24 The reaction proved to be trouble-
5. Mealy, N. E.; Castaner, R. M.; Silvestre, J. Drugs Future 2001, 26, 1139–1148.
6. Goeschke, R.; Stutz, S.; Heinzelmann, W.; Maibaum, J. Helv. Chim. Acta 2003, 86,
2848–2870.
7. Rueer, H.; Stutz, S.; Goeschke, R.; Spindler, F.; Maibaum, J. Tetrahedron Lett.
2000, 41, 10085–10090.
8. Sandham, D. A.; Taylor, R. J.; Carey, J. S.; Fassler, A. Tetrahedron Lett. 2000, 41,
10091.
9. Herold, P.; Stutz, S. WO 02/08172, January 31, 2002.
10. Dondoni, A.; De Lathaurver, G.; Perrone, D. Tetrahedron Lett. 2001, 42, 4819.
11. Hanessian, S.; Claridge, S.; Johnstone, S. J. Org. Chem. 2002, 67, 4261.
12. Lindsay, K. B.; Skrydstrup, T. J. Org. Chem. 2006, 71, 4766–4777.
13. Krapcho, A. P. Synthesis 1982, 805, 893.
14. Evans, D. A.; Takacs, J. M. Tetrahedron Lett. 1980, 21, 4233.
15. Evans, D. A.; Bartoli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127.
16. For a similar oxidative cleavage using ozone, see: Clive, D. L. J.; Murthy, D. K. S.
K.; Wee, A. G. H.; Prasad, J. S.; da Silva, G. V. J.; Majewski, M.; Anderson, P. C.;
Evans, C. F.; Haugen, R. D.; Heerze, L. D.; Barrie, J. R. J. Am. Chem. Soc. 1990, 112,
3018–3028.
17. Abiko, A.; Masamune, A. J. Am. Chem. Soc. 1997, 119, 2586–2587.
18. Lafontaine, J. A.; Provencal, D. P.; Gardelli, C.; Leahy, J. W. J. Org. Chem. 2003, 68,
4215–4234.
19. Evans, D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre, D. J.; Bartoli, J.
Pure Appl. Chem. 1981, 53, 1109.
some due to the formation of
a side product, which was
identified as the cyclic urea 20. The formation of this impurity
was significant when the reaction was carried out for a prolonged
period (4 days). By carrying out the reaction to 90% completion, it
was possible to obtain the desired product 19 in 66% yield with
only minor amounts of the urea 20 being formed. Finally, aliskiren
(1) was obtained from 19 by hydrogenolysis. The NMR and mass
spectral data for the target molecule matched those reported in
the literature.1–3 The yield for this step was 97%. A summary of
the last three steps is shown in Scheme 6.
20. Valluri, M.; Hindupur, R. M.; Bijory, P.; Labadie, G.; Jung, J.-C.; Avery, M. A. Org.
Lett. 2001, 3, 3607–3609.
21. Evans, D. A.; Kim, A. S.; Metternich, R.; Novack, V. J. J. Am. Chem. Soc. 1998, 120,
5921–5942.
In summary, aliskiren has been synthesized in 12 steps starting
from the chiral chloride 1 (Scheme 1). The overall yield (taking into
account the longest linear path) was 3.3%.
22. Kiho, T.; Nakayama, M.; Kogen, H. Tetrahedron 2003, 59, 1685–1697.
23. Sibi, M. P.; Lu, J.; Edwards, J. J. Org. Chem. 1997, 62, 5864–5872.
24. Foley, M. S.; Jamison, T. F. Org. Process Res. Dev. 2010, 14, 1177.