Facile synthesis of 4-substituted-4-aminopiperidine derivatives, the key building block of piperazine-based CCR5 antagonists

Article abstract of DOI:10.1016/j.bmcl.2004.05.014

4-Substituted-4-aminopiperidine is an interesting structural motif found in a number of bioactive compounds. An efficient and convenient method for the synthesis of 4-differently substituted-4-aminopiperidine derivatives was described, employing isonipecotate as a starting material and Curtius rearrangement as a key step. The alkylation of isonipecotate could introduce various substituents at the 4-position of the piperidine ring. With this key building block, we are able to efficiently synthesize piperazino-piperidine based CCR5 antagonist in a highly convergent manner free of using toxic reagents such as diethylaluminum cyanide. The concise synthesis of a potent bioavailable CCR5 antagonist as HIV-1 entry inhibitor, Sch-350634 (1) was accomplished in excellent yield using N′-Boc-4-methyl-4-aminopiperidine 5a as a smart building block. The new methodology provides a facile and practical access to the piperazino-piperidine amide analogs as HIV-1 entry inhibitors.

Full text of DOI:10.1016/j.bmcl.2004.05.014

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3675–3678
Facile synthesis of 4-substituted-4-aminopiperidine derivatives,
the key building block of piperazine-based CCR5 antagonists
Xiao-Hua Jiang, Yan-Li Song and Ya-Qiu Long*
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences,
CAS, 555 Zuchongzhi Road, Shanghai 201203, China
Received 16 April 2004; revised 28 April 2004; accepted 10 May 2004
Available online 2 June 2004
Abstract—4-Substituted-4-aminopiperidine is an interesting structural motif found in a number of bioactive compounds. An effi-
cient and convenient method for the synthesis of 4-differently substituted-4-aminopiperidine derivatives was described, employing
isonipecotate as a starting material and Curtius rearrangement as a key step. The alkylation of isonipecotate could introduce various
substituents at the 4-position of the piperidine ring. With this key building block, we are able to efficiently synthesize piperazino-
piperidine based CCR5 antagonist in a highly convergent manner free of using toxic reagents such as diethylaluminum cyanide. The
concise synthesis of a potent bioavailable CCR5 antagonist as HIV-1 entry inhibitor, Sch-350634 (1) was accomplished in excellent
yield using N0-Boc-4-methyl-4-aminopiperidine 5a as a smart building block. The new methodology provides a facile and practical
access to the piperazino-piperidine amide analogs as HIV-1 entry inhibitors.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
nists.5 As part of our program to further refine com-
pounds in the two families for improved potency, higher
selectivity, and good ADME properties, development of
convenient synthesis of the structurally diverse pipe-
razino-piperidine amide analogs in laboratory is re-
quired. With N0-Boc-4-substituted-4-aminopiperidine as
a key building block, we established an efficient and
short synthesis of the piperazino-piperidine core struc-
ture in a convergent manner. Herein we would like to
report our newly developed methodology to synthesize
4-subtituted-4-aminopiperidine derivatives and its typi-
cal application in the concise synthesis of a potent, or-
ally-active CCR5 antagonist, Sch-350634 (1).
Interest in 4-subtituted-4-aminopiperidine derives from
the varied biological activity of this structural motif
containing compounds, which were evaluated as nar-
cotic analgesics,1 muscarinic M3 receptor antagonists,2
neurokinin-1 receptor ligands,3 5-HT2A serotonin
receptor antagonists,4 and CCR5 chemokine receptor
ligands.5 Among them, the most attractive pharmaco-
logical class is the piperidine-based CCR5 antagonists,
as exemplified by the compounds in Figure 1. CCR5, a
co-receptor essential for HIV-1 recognition and entry
into CD4+ macrophages and T-cells,6 is a highly vali-
dated target for the treatment of HIV-1 infection.7 A
proof of concept for this approach has been provided by
Sch-C and Sch-D, two CCR5 receptor antagonists as
HIV-1 entry inhibitors under clinical trials.8
2. Results and discussion
According to the literature, three approaches were re-
ported to prepare the 4-substituent-4-aminopiperidine
derivatives starting from 4-piperidone. One method in-
volved the Ritter reaction as the key step (large amount
of concd H2SO4 is needed),1b;9 the second employed
highly toxic cyanide reagent in the Strecker amino nitrile
synthesis followed by a hydration,3a;10 and the third re-
quired nucleophilic addition of alkylmagnesium bro-
mide (the type of alkyl group is limited) to the in situ-
generated imine from the condensation of the N-Boc-4-
piperidone with amine.11
Currently, piperidine- and piperazine-based compounds
disclosed by Schering–Plough Research Institute are an
attractive and promising class of potent CCR5 antago-
Keywords: 4-Substituted-4-aminopiperidine; Piperazine-based CCR5
antagonist; Curtius rearrangement; Building block; Convergent syn-
thesis; HIV-1 entry inhibitor.
* Corresponding author. Tel.: +86-21-50806600; fax: +86-21-508068-
76; e-mail: yqlong@mail.shcnc.ac.cn
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.05.014

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X.-H. Jiang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3675–3678
Figure 1. Piperidine- and piperazine-based CCR5 antagonists.
The versatile building block requires a reliable route
to an orthogonally-protected piperidine suitably for
different synthetic strategy toward various bioactive
molecules containing the scaffold of 4-substituent-
4-aminopiperidine. Therefore, we developed a new
methodology to generate orthogonally-protected 4-
substituent-4-aminopiperidine conveniently from com-
mercially available isonipecotic acid, with flexible
substitution at the 4-position of the piperidine ring.
protected 4-substituent-4-aminopiperidine 5. The over-
all yield of the four steps could reach up to 89%. Initial
attempts to hydrolyze the isocyanate in 2 N NaOH re-
sulted in the formation of a symmetrical urea as a major
product. We increased the concentration of KOH
aqueous solution till 10 N and harvested the desired
amine product.13
We also developed an operationally simple, high-yield
approach for the synthesis of N0-Boc-4-aminopiperidine
5e, not having a 4-substituent. This widely-used synthon
was readily prepared by a facile reductive amination of
commercially available N-Boc-piperidone with H2 and
catalytic 10% Pd–C in the NH3-saturated methanol in
yield of 84%.
As shown in Scheme 1, isonipecotic acid was protected
under standard conditions to give N-Boc-isonipecotate
(2) in excellent yield. Introduction of various group at
the 4-position was achieved via alkylation of the lithium
enolate with either alkyl or aryl halide in THF. The
resulting N-Boc-4-substituted-isonipecotic acid ethyl
ester 3a was hydrolyzed to give the corresponding acid
4a using 2 N lithium hydroxide in methanol at room
temperature. For the hydrolysis of 4-substituted isoni-
pecotic acid methyl ester 3b–d, it was found more
effective to use 2 N potassium hydroxide in refluxing
methanol. Conversion of the acid to the desired product
Compared to those previously reported procedures, the
newly developed methodology is flexible and allows for
preparing a variety of 4-aminopiperidine derivatives
with different functional group at 4-position of the
piperidine ring and orthogonal protecting group at the
N0 position. To our knowledge, this is the most versatile
and facile approach to the synthesis of 4-substituent-4-
aminopiperidine derivatives reported to date, and the
suitably protected N0-Boc-4-methyl-4-aminopiperidine
is a very useful building block for the syntheses of
piperazino-piperidine containing CCR5 antagonists.
N0-Boc-4-substituent-4-aminopiperidine
5
proceeded
smoothly via Curtius rearrangement with 4 operations
in one pot.12;13 First, N-Boc-4-substituted-isonipecotic
acid 4 was activated by forming mixed anhydride with
isobutyl chloroformate in basic condition. Then, treat-
ment of the resulting anhydride with sodium azide
followed by thermolysis in toluene afforded the N-Boc-
4-substituent-4-isocyanate, which was hydrolyzed in
strong basic conditions to furnish the orthogonally-
The literature-reported synthesis of the aryl piperazino-
piperidine amide analogs as CCR5 antagonists was
accomplished via SN2 displacement route or diketopip-
Scheme 1. General synthetic scheme of the versatile building block, N0-Boc-4-substituted-4-aminopiperidine. Reagents and conditions: (a) LDA,
)78 °C, CH3I or RBr, THF; (b) 2 N LiOH CH3OH, rt or 2 N KOH, reflux (for 3b–d); (c) ClCOOiBu, NMM, THF, )15 °C, 1 h; (d) NaN3, THF–
H2O, )15 °C, 1 h then rt overnight; (e) toluene, 90 °C, 1.5 h; (f) 10 N KOH, THF–H2O, 0 °C; (g) H2, 10% Pd/C, NH3/CH3OH, rt, 84.0%.

X.-H. Jiang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3675–3678
3677
Scheme 2. Convergent synthesis of Sch-350634 (1), a potent and orally active CCR5 antagonist employing N0-Boc-4-methyl-4-aminopiperidine (5a)
as a building block. Reagents and conditions: (a) ClCH2COCl, 1,2-dichloroethane, reflux, 96%; (b) (i) 5a, DIPEA, CH3CN, reflux, 80%; (ii) catalytic
2-pyridinol, toluene, 90 °C, 84%; (c) (i) TFA, CH2Cl2, rt; (ii) NaBH4, BF3ÆEt2O, dimethoxy ethane, reflux; (d) 2,4-dimethylnicotinic acid-N-oxide,
EDCI, HOBT, DIPEA, CH2Cl2, rt, overall yield of 47% (three steps for c and d).
erazine route,14;15 in which the piperazino-piperidine
nucleus was constructed by a linear synthetic strategy
and the pharmacophore group at 4-position of the
piperidine was introduced by a modified Strecker reac-
tion using toxic diethylaluminum cyanide.
ous substituents at the important 4-position of the
piperidine.
3. Conclusion
With N0-Boc-4-substituent-4-aminopiperidine in hand,
we envisioned that the backbone of piperazino-piperi-
dine series CCR5 antagonists could be assembled in a
highly convergent manner via a nucleophilic substitu-
tion followed by a lactamization of chloro-substituted
acetyl methyl ester 7 with this key building block 5. A
convergent synthesis of the potent and orally active
CCR5 antagonist of Sch-350634 (1) (Scheme 2) was ta-
ken as an example to demonstrate the general procedure
to prepare structurally diverse piperidino-piperazine
amides with building block 5.
In summary, we have developed a new method to syn-
thesize
a series of 4-substituted-4-aminopiperidine
derivatives employing commercially available isonip-
ecotate as a starting material and Curtius rearrangement
as a key step. The key building block was successfully
applied to an efficient synthesis of piperazino-piperidine
based CCR5 antagonist in a highly convergent manner
free of using toxic reagents such as diethylaluminum
cyanide. The concise synthesis of a potent bioavailable
CCR5 antagonist as HIV-1 entry inhibitor, Sch-350634
(1) was accomplished in excellent yield using N0-Boc-4-
methyl-4-aminopiperidine 5a as a smart building block.
The newly developed methodology provides us with a
facile and practical access to the structurally diverse
piperazino-piperidine compounds as CCR5 antagonists,
thus potentially benefits the development of the HIV-1
entry inhibitors into new anti-AIDS drugs.
According to Scheme 2, compound 6, which was pre-
pared following a literature precedent,14;15 was treated
with 2-chloroacetyl chloride in refluxing 1,2-dichloro-
ethane to give the corresponding (2-chloroacetyl)-ami-
no-acetic acid methyl ester 7 in yield of 96%. The
nucleophilic substitution of 7 with the free amine of the
building block 5a followed by an intramolecular N-
acylation reaction in the presence of catalytic 2-pyridi-
nol afforded the aryl diketopiperazino-piperidine 8 in an
overall yield of 67.2%.16 It was noted that the product of
the nucleophilic displacement in the refluxing methanol
could not undergo the subsequent intramolecular cycli-
zation simultaneously under the same reaction condi-
tion. We isolated the intermediate and heated it with
catalytic 2-pyridinol in toluene at 90 °C for 6 h to pro-
duce the diketopiperazine product 8 as a single stereo-
isomer.17 Boc removal with trifluoroacetic acid and
subsequent reduction with NaBH4 gave the aryl pipe-
razino-piperidine analog 9. The coupling of the resulting
free amine 9 with the desired aromatic acids proceeded
under standard conditions to furnish the desired product
1.18 Obviously, by using 4-methyl-piperidin-4-ylamine as
a key synthon, we simplify the construction of the nu-
cleus of the piperazino-piperidine amide analogs via one
step reaction, furthermore, our developed methodology
is devoid of the highly toxic and flammable reagent
such as diethylaluminum cyanide employed by the
Schering–Plough’s modified Strecker reaction, and
provides potential for convenient introduction of vari-
Acknowledgements
Financial supports from Shanghai Municipal Commit-
tee of Science and Technology, China (02QB14056 and
03DZ19219) and the Chinese Academy of Sciences
(STZ-01-27 and KSCX1-SW-11) are greatly appreci-
ated.
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