A two-step, one pot preparation of amines via acyl succinimides. Synthesis of the calcimimetic agents cinacalcet, NPS R-467, and NPS R-568

Article abstract of DOI:10.1016/j.tetlet.2015.05.095

Abstract A method has been developed for the preparation of amines through a process of coupling acyl succinimides derived from commercially available carboxylic acids with amines to afford the corresponding amides. These amides are then reduced in situ with either diisobutylaluminum hydride or lithium aluminum hydride. The reaction tandem of the coupling reaction followed by the reduction affords the amine in fair to good yields after purification by flash chromatography. This one-pot, two reaction tandem process has been successfully applied to the synthesis of the calcimimetic agents cinacalcet, NPS R-467, and NPS R-568.

Full text of DOI:10.1016/j.tetlet.2015.05.095

Tetrahedron Letters 56 (2015) 4468–4471
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A two-step, one pot preparation of amines via acyl succinimides.
Synthesis of the calcimimetic agents cinacalcet, NPS R-467, and NPS
R-568
Cassie A. Gooodman, Elise Marie Janci, Olivia Onwodi, Chad C. Simpson, Christopher G. Hamaker,
⇑
Shawn R. Hitchcock
Department of Chemistry, Illinois State University, Normal, IL 61790-4160, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A method has been developed for the preparation of amines through a process of coupling acyl succin-
imides derived from commercially available carboxylic acids with amines to afford the corresponding
amides. These amides are then reduced in situ with either diisobutylaluminum hydride or lithium alu-
minum hydride. The reaction tandem of the coupling reaction followed by the reduction affords the
amine in fair to good yields after purification by flash chromatography. This one-pot, two reaction tan-
dem process has been successfully applied to the synthesis of the calcimimetic agents cinacalcet, NPS
R-467, and NPS R-568.
Received 15 May 2014
Revised 22 May 2015
Accepted 26 May 2015
Available online 30 May 2015
Keywords:
Succinimide
Cinacalcet
Ó 2015 Elsevier Ltd. All rights reserved.
NPS R-467
NPS R-568
Acyl succinimide
Reductive amination
Acyl succinimides are activated amides that can be readily pre-
pared by the reaction of acyl chlorides with succinimide or by the
reaction of carboxylic acids with carbodiimides and succinimide.1
These compounds have received little attention, but have the
potential for use in a variety of applications. Reductive amination
is one of the most common methods employed for the synthesis
of amines. There was interest in employing the acyl succinimides
in a two-step, one pot process for the synthesis of amines by an
acyl coupling/reduction tandem (Fig. 1). The process would be a
carboxyl equivalent of reductive amination.2 The utility in this
methodology would involve the conversion of the carboxylic acid
into an acyl succinimide for the coupling/reduction process. This
would potentially require less work than converting the carboxylic
acid to the aldehyde for the purpose of a reductive amination. This
methodology would not be viable with other carboxyl derivatives.
The formation of an amide from an acyl chloride3 and an amine
would generate the protonated scavenger base (e.g., Et3NHCl) that
would react violently with any reducing agents in the second stage
of the reaction. Another example of an incompatible process would
involve the use of a carbodiimide (e.g., DCC, DMAP) to couple a car-
boxylic acid and an amine.4 The resultant amide would be formed
along with N,N0-dicyclohexylurea. The urea side product would
react with any reducing agent and would complicate the reaction
mixture. Activated esters such as p-nitrophenyl esters,5 N-hydrox-
ysuccinimide esters,6 or acyl imidazoles7 would also involve prob-
lematic features, primarily the byproducts of the acyl coupling
reacting with the reducing agent. In contrast, acyl succinimides
can be easily prepared from carboxylic acids and readily undergo
coupling with amines to afford the corresponding amide with suc-
cinimide as the only side product. These combined factors would
be optimal for a one-pot process of coupling and reduction. The
process of conducting the coupling/reduction tandem reactions in
a single vessel is described as well as the synthesis of the cal-
cimimetic agents cinacalcet (sensiparÒ), NPS R-467 and NPS R-568.
This work began with the preparation of 3-phenylpropanoyl
succinimide (7) as a model compound for the acyl coupling/reduc-
tion tandem. This succinimide was prepared in 70% yield by the
reaction of 3-phenylpropanoic acid with EDC, DMAP, and succin-
imide (Scheme 1). There was also interest in forming the acyl suc-
cinimide of 3,4-dimethoxyphenylacetic acid as this compound
would serve as a potential intermediate in the synthesis of the
anti-arrhythmic agent denopamine.8 Under the conditions that
were employed, this carboxylic acid formed diketone 9. This was
unexpected and may have occurred through a process of formation
of the activated acyl DMAP derivative followed by a Claisen type
condensation and concomitant decarboxylation. The formation of
⇑
Corresponding author. Tel.: +1 309 438 7854; fax: +1 3009 438 5538.
E-mail address: Hitchcock@illinoisstate.edu (S.R. Hitchcock).
http://dx.doi.org/10.1016/j.tetlet.2015.05.095
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

C. A. Gooodman et al. / Tetrahedron Letters 56 (2015) 4468–4471
4469
O
O
amine (R)-12 with the phenylpropanoic acid derivative 22 to form
an amide that is isolated and then subsequently reduced
(Scheme 2).9–13
O
coupling method
R
N
R
OH
O
O
N
H
O
1
3
2
Ortiz-Marciales and co-workers developed a method for the
asymmetric synthesis of non-racemic primary amines based on
an amido-spiroborate catalyzed reduction of O-benzyloximes.11
This methodology was used to synthesize the necessary amine
(R)-12. With the amine in hand, they were able to prepare cinacal-
cet using an efficient coupling pathway followed by a reduction.
Other methods directed at the preparation of cinacalcet require
the same number of steps or more.14,15
Two step, one pot tandem
O
R'NH2
reduction
3
R
NHR'
R
NHR'
4
5
+ succinimide (2)
The advantage of the acyl succinimide method is that the amine
component of the coupling reaction is carried through two chem-
ical transformations in a single vessel. The chiral amine is usually
the more expensive component of the reaction. Ultimately, it
would be beneficial for the amine to be used in as few synthetic
steps as possible. In this context, the synthesis of cinacalcet using
the tandem one-pot acyl succinimide coupling/reduction pathway
was explored (Scheme 3). The acyl succinimide was first prepared
from commercially available trans-(3-trifluoromethyl)-3-phenyl-
propenoic acid (22). This material was treated with H2 over Pd/C
to afford the corresponding 3-(trifluoromethyl)-3-phenyl-
propanoic acid (23) in 85% yield. The carboxylic acid was then con-
verted to the 3-phenylpropanoyl succinimide 24 by reaction with
EDC, DMAP, and succinimide. This process yielded 24 as a crys-
talline solid in 44% isolated yield after recrystallization. The succin-
imide was then treated with (R)-1-naphthylethylamine (12) and
stirred for 18 h. The reaction mixture was then treated with
Dibal-H and stirred overnight at reflux. The target cinacalcet (25)
was obtained in 54% yield after flash chromatography. The acyl
Figure 1. Reductive amination with acyl succinimides.
the corresponding diketone was not observed in the case of the for-
mation of the 3-phenylpropanoyl succinimide suggesting that this
was limited to this substrate.
With acyl succinimide 7 in hand, the tandem process of the cou-
pling reaction and the reduction of the amide in situ was explored
(Table 1). To this end, acyl succinimide 7 was reacted with amines
10–15 for 18 h at the end of which Dibal-H (8 equiv) (entries 1–3)
or lithium aluminum hydride (entries 4–6) was added dropwise.
The temperature was raised to reflux for 18 h. The overall process
was successful and yielded the desired amines 16–21 in a two-
step, one-pot process in yields ranging between 42% and 72%.
Cinacalcet (24) is a calcimimetic agent used to treat secondary
hyperparathyroidism and has been previously synthesized by a
variety of methods including a reductive amination pathway
involving the Forster reaction. The principle method that has been
used to prepare cinacalcet has involved the coupling of the chiral
O
O
O
O
O
N
H
Ph
N
Ph
OH
O
EDC, DMAP
7
6
8
O
O
O
N
H
H3CO
H3CO
H3CO
O
9
EDC, DMAP
H3CO
OH
OCH3
OCH3
Scheme 1. Unexpected symmetrical ketone formation and X-ray crystal structure of 9.

4470
C. A. Gooodman et al. / Tetrahedron Letters 56 (2015) 4468–4471
Table 1
Two step, one pot synthesis of amines from acyl succinimides
O
RNH2, THF
Dibal-H (8 eq.)
or LiAlH4 (4 eq.)
NHR
NHR
7
16-21
10-15
not isolated
+
succinimide
Entry
Amine
Product
Yielda
1
2
3
4
5
6
p-CH3OC6H4NH2 (10)
1-C6H5CH(CH3)NH2 (11)
1-C8H7CH(CH3)NH2 (12)
Morpholine (13)
16
17
18
19
20
21
42
64
54
72
71
52
Pyrrolidine (14)
L
-Phenylalaninol (15)
a
Isolated chemical yield after flash chromatography.
H3C
NH2
coupling
HO
+
CF3
synthetic methods
ref.10-13
O
22
(R)-12
H
N
H
N
H3C
H3C
CF3
reduction
CF3
O
23
cinacalcet (24)
Scheme 2. Syntheses of cinacalcet (21).
CO2H
CO2H
H2, Pd/C, THF
There was a concern that the trifluoromethyl group might be sus-
ceptible to over reduction. However, Ono and co-workers had
demonstrated that this moiety is stable to such reduction condi-
tions.17 The use of lithium aluminum hydride as a powder gave
inconsistent results after numerous trials. In contrast, a solution
of lithium aluminum hydride (2 M in THF) gave results that were
much improved as multiple runs yielded consistent results
(Scheme 3).
We were gratified to learn that the two-step, one pot reaction
worked well and yielded cinacalcet in 57% yield. The process
proved to be consistent and reproducible and only required a sin-
gle reaction vessel to achieve the synthesis of the product. It was at
this point that we considered demonstrating the utility of this pro-
cess by applying it to other calcimimetic agents.
NPS R-467 (27) and NPS R-568 (31) are calcimimetic agents that
have been described in the literature18 and have been prepared by
a variety of methods.19–28 The most common method of prepara-
tion of these amines was the coupling of a carboxylic acid with
the necessary chiral amine fragment followed by a second reaction
(reduction). The current method of the two-step, one pot method
was applied to the synthesis of NPS R-467 and NPS R-568. NPS
R-467 was prepared in this manner by reacting acyl succinimide
(7) with (R)-3-methoxy phenyl ethylamine [(R)-26] followed by
reduction with lithium aluminum hydride yielding the target
NPS R-467 in 71% yield after purification (Scheme 4).
With the success and improved yield for the process, the two-
step, one pot tandem was then applied to the preparation of NPS
R-568. Thus, 3-(2-chlorophenyl)propanoic acid was treated with
EDC, DMAP, and succinimide to generate propanoyl succinimide
29 in 82% yield (Scheme 5). The yield was 60% when the reaction
85%
22
(95%,mutl-gram scale)
23
CF3
CF3
O
O
O
O
O
N
N
H
23
EDC, DMAP, THF
44%
24
CF3
H3C
(53%, multi-gram scale)
H3C
NH2
H
N
CF3
(R)-12
1a.
24
25
1b. Dibal-H(8 equiv.);54%
multi-gram scaleLiAlH4 (4 equiv.);57%
Scheme 3. Synthesis of cinacalcet via an acyl succinimide approach.
succinimide–Dibal-H reduction pathway was successful, but the
yield of the two-step, one pot synthesis was optimized to 54%. In
addition to this, the reaction was capricious in terms of the isolated
chemical yield. At this stage, the use of an alternate reducing agent
was considered in order to circumvent the difficulties associated
with the use of Dibal-H. The application of borane (BH3–THF,
BH3–DMS, NaBH4, I2) as a reducing agent failed to generate the
product. In contrast, lithium aluminum hydride was considered
to be ideal for the removal of the succinimide by its reduction to
its corresponding pyrrolidine or the 4-aminobutanol derivative.16

C. A. Gooodman et al. / Tetrahedron Letters 56 (2015) 4468–4471
4471
CH3
OCH3
CH3
H2N
OCH3
1a.
(R)-26
N
H
7
1b. LiAlH4, THF (4 equiv.)
27
71%
Scheme 4. Two-step, one pot synthesis of NPS R-467.
References and notes
O
O
O
O
O
O
N
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Scheme 5. Two-step, one pot synthesis of NPS R-568.
was carried out on a multi-gram scale. The acyl succinimide was
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Acknowledgements
The authors acknowledge technical assistance from Delvis D.
Dore, Jesse A. Wolfe, and Dipak Patel. The authors acknowledge
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University. Accurate mass electrospray ionization (ESI) mass spec-
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acquired through support by the National Science Foundation
MRI Program under Grant No. CHE 1337497.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.05.
095.